Lena Carlsson

Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality.The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%).The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29).Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.

Obesity is a risk factor for cardiovascular events. Weight loss might protect against cardiovascular events, but solid evidence is lacking.To study the association between bariatric surgery, weight loss, and cardiovascular events.The Swedish Obese Subjects (SOS) study is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2037 contemporaneously matched obese controls who received usual care. Patients were recruited between September 1, 1987, and January 31, 2001. Date of analysis was December 31, 2009, with median follow-up of 14.7 years (range, 0-20 years). Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Exclusion criteria were identical in surgery and control patients. Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system. Physical and biochemical examinations and database cross-checks were undertaken at preplanned intervals.The primary end point of the SOS study (total mortality) was published in 2007. Myocardial infarction and stroke were predefined secondary end points, considered separately and combined.Bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2010 patients in the surgery group vs 49 events among 2037 patients in the control group; adjusted hazard ratio [HR], 0.47; 95% CI, 0.29-0.76; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2010 patients) than in the control group (234 events among 2037 patients; adjusted HR, 0.67; 95% CI, 0.54-0.83; P < .001).Compared with usual care, bariatric surgery was associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults.

Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known.To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery.The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1, 1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively.Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group.Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose <110 mg/dL and no diabetes medication.The diabetes remission rate 2 years after surgery was 16.4% (95% CI, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% CI, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% CI, 8.5-20.7; P < .001). At 15 years, the diabetes remission rates decreased to 6.5% (4/62) for control patients and to 30.4% (35/115) for bariatric surgery patients (OR, 6.3; 95% CI, 2.1-18.9; P < .001). With long-term follow-up, the cumulative incidence of microvascular complications was 41.8 per 1000 person-years (95% CI, 35.3-49.5) for control patients and 20.6 per 1000 person-years (95% CI, 17.0-24.9) in the surgery group (hazard ratio [HR], 0.44; 95% CI, 0.34-0.56; P < .001). Macrovascular complications were observed in 44.2 per 1000 person-years (95% CI, 37.5-52.1) in control patients and 31.7 per 1000 person-years (95% CI, 27.0-37.2) for the surgical group (HR, 0.68; 95% CI, 0.54-0.85; P = .001).In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01479452.

Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.).

Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data.The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] >or=34 kg/m(2) in men, and >or=38 kg/m(2) in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99.9% and the median follow-up time was 10.9 years (range 0-18.1 years).Bariatric surgery resulted in a sustained mean weight reduction of 19.9 kg (SD 15.6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1.3 kg (SD 13.7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0.67, 95% CI 0.53-0.85, p=0.0009). The sex-treatment interaction p value was 0.054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0.58, 0.44-0.77; p=0.0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0.97, 0.62-1.52; p=0.90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention.Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men.Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+/-3.54 microm) and large cells (mean 100.1+/-3.94 microm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.

Obesity shortens life expectancy. Bariatric surgery is known to reduce the long-term relative risk of death, but its effect on life expectancy is unclear.

Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity. Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts1,2,3,4. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte‐specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome‐scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809 , enables mechanistic insights into adipocyte metabolism on a genome‐wide level, and can serve as a scaffold for integration of omics data to understand the genotype–phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling.

Obesity is a risk factor for atrial fibrillation, which in turn is associated with stroke, heart failure, and increased all-cause mortality. The authors investigated whether weight loss through bariatric surgery may reduce the risk of new-onset atrial fibrillation. SOS (Swedish Obese Subjects) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary healthcare centers in Sweden. The cohort was recruited between 1987 and 2001. Among 4,021 obese individuals with sinus rhythm and no history of atrial fibrillation, 2,000 underwent bariatric surgery (surgery group), and 2,021 matched obese control subjects received usual care (control group). The outcome, first-time atrial fibrillation, was ascertained by crosschecking the SOS database with the Swedish National Patient Register on inpatient and outpatient diagnosis codes. During a median follow-up of 19 years, first time atrial fibrillation occurred in 247 patients (12.4%) in the surgical group, and in 340 (16.8%) control subjects. The risk of developing atrial fibrillation was 29% lower in the surgery group versus the control group (hazard ratio: 0.71; 95% confidence interval: 0.60 to 0.83; p < 0.001). Younger individuals benefited more from surgical intervention than those who were older (p value for interaction 0.001). Also, those with a high diastolic blood pressure benefitted more from surgery than did those with a low diastolic blood pressure (p for interaction = 0.028). Compared with usual care, weight loss through bariatric surgery reduced the risk of atrial fibrillation among persons being treated for severe obesity. The risk reduction was more apparent in younger people and in those with higher blood pressure.

Eligibility criteria for bariatric surgery in diabetes include BMI ≥35 kg/m(2) and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified.Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD).Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission (P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders.Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI.

Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein.We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene.Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor.Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.

Accumulation of visceral fat is recognized as a predictor of obesity-related metabolic disturbances. Factors that are predominantly expressed in this depot could mediate the link between visceral obesity and associated diseases.Paired subcutaneous and omental adipose tissue biopsies were obtained from 10 obese men. Gene expression was analyzed by DNA microarrays in triplicate and by real-time polymerase chain reaction. Serum C3 and C4 were analyzed by radial immunodiffusion assays in 91 subjects representing a cross section of the general population. Body composition was measured by computerized tomography.Complement components C2, C3, C4, C7, and Factor B had higher expression in omental compared with subcutaneous adipose tissue ( approximately 2-, 4-, 17-, 10-, and 7-fold, respectively). In addition, adipsin, which belongs to the alternative pathway, and the classical pathway components C1QB, C1R, and C1S were expressed in both depots. Analysis of tissue distribution showed high expression of C2, C3, and C4 in omental adipose tissue, and only liver had higher expression of these genes. Serum C3 levels correlated with both visceral and subcutaneous adipose tissue in both men (r = 0.65 and p < 0.001 and r = 0.52 and p < 0.001, respectively) and women (r = 0.34 and p = 0.023 and r = 0.49 and p < 0.001, respectively), whereas C4 levels correlated with only visceral fat in men (r = 0.36, p = 0.015) and with both depots in women (visceral: r = 0.58, p < 0.001; and subcutaneous: r = 0.51, p < 0.001).Recent studies show that the metabolic syndrome is associated with chronically elevated levels of several immune markers, some of which may have metabolic effects. The high expression of complement genes in intra-abdominal adipose tissue might suggest that the complement system is involved in the development of visceral adiposity and/or contributes to the metabolic complications associated with increased visceral fat mass.

The size of body fat stores is known to influence fertility, indicating a link between adipose tissue and the reproductive system. Studies in mice have identified the adipocyte-derived hormone, leptin (Ob protein), as a possible mediator of this effect. The aim of this study was to investigate the possibility that leptin may have direct effects on the human ovary. To probe this hypothesis we first analyzed the expression of leptin receptors in the human ovary. Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells and thecal cells; however, the short isoforms were expressed at much higher levels. Immunoreactive leptin was present in follicular fluid at levels similar to those found in serum. ob gene expression, however, was undetectable in the ovary, as determined by reverse transcription-PCR, whereas it was easily detected in adipose tissue. To determine whether leptin could induce a biological response in ovarian cells, we examined the effect of leptin on estradiol production in cultured granulosa cells. Leptin (100 ng/mL) inhibited LH (0.1 ng/mL)-stimulated estradiol production. In contrast, leptin had no effect on estradiol production in the absence of LH. In conclusion, this study has demonstrated that the leptin receptor is expressed in the human ovary, that leptin is present in follicular fluid, and that leptin can induce a biological response in ovarian cells. These results suggest that leptin may have a direct effect on the human ovary.

Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells.Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in beta-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of beta-oxidation, whereas the accumulation of triglycerides increased.The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.

Obese individuals with type 2 diabetes have an increased risk of cardiovascular disease. The effect of bariatric surgery on cardiovascular events in obese individuals with type 2 diabetes remains to be determined. The Swedish Obese Subjects (SOS) study is a prospective, controlled intervention study that examines the effects of bariatric surgery on hard end points. The aim of the present study was to examine the effect of bariatric surgery on cardiovascular events in the SOS study participants with type 2 diabetes.All SOS study participants with type 2 diabetes at baseline were included in the analyses (n = 345 in the surgery group and n = 262 in the control group). Mean follow-up was 13.3 years (interquartile range 10.2-16.4) for all cardiovascular events.Bariatric surgery was associated with a reduced myocardial infarction incidence (38 events among the 345 subjects in the surgery group vs. 43 events among the 262 subjects in the control group; log-rank P = 0.017; adjusted hazard ratio [HR] 0.56 [95% CI 0.34-0.93]; P = 0.025). No effect of bariatric surgery was observed on stroke incidence (34 events among the 345 subjects in the surgery group vs. 24 events among the 262 subjects in the control group; log-rank P = 0.852; adjusted HR 0.73 [0.41-1.30]; P = 0.29). The effect of surgery in reducing myocardial infarction incidence was stronger in individuals with higher serum total cholesterol and triglycerides at baseline (interaction P value = 0.02 for both traits). BMI (interaction P value = 0.12) was not related to the surgery outcome.Bariatric surgery reduces the incidence of myocardial infarction in obese individuals with type 2 diabetes. Preoperative BMI should be integrated with metabolic parameters to maximize the benefits of bariatric surgery.

Bariatric surgery results in sustained weight loss; reduced incidence of diabetes, cardiovascular events, and cancer; and improved survival. The long-term effect on health care use is unknown.To assess health care use over 20 years by obese patients treated conventionally or with bariatric surgery.The Swedish Obese Subjects study is an ongoing, prospective, nonrandomized, controlled intervention study conducted in the Swedish health care system that included 2010 adults who underwent bariatric surgery and 2037 contemporaneously matched controls recruited between 1987 and 2001. Inclusion criteria were age 37 years to 60 years and body mass index of 34 or higher in men and 38 or higher in women. Exclusion criteria were identical in both groups.Of the surgery patients, 13% underwent gastric bypass, 19% gastric banding, and 68% vertical-banded gastroplasty. Controls received conventional obesity treatment.Annual hospital days (follow-up years 1 to 20; data capture 1987-2009; median follow-up 15 years) and nonprimary care outpatient visits (years 2-20; data capture 2001-2009; median follow-up 9 years) were retrieved from the National Patient Register, and drug costs from the Prescribed Drug Register (years 7-20; data capture 2005-2011; median follow-up 6 years). Registry linkage was complete for more than 99% of patients (4044 of 4047). Mean differences were adjusted for baseline age, sex, smoking, diabetes status, body mass index, inclusion period, and (for the inpatient care analysis) hospital days the year before the index date.In the 20 years following their bariatric procedure, surgery patients used a total of 54 mean cumulative hospital days compared with 40 used by those in the control group (adjusted difference, 15; 95% CI, 2-27; P = .03). During the years 2 through 6, surgery patients had an accumulated annual mean of 1.7 hospital days vs 1.2 days among control patients (adjusted difference, 0.5; 95% CI, 0.2 to 0.7; P < .001). From year 7 to 20, both groups had a mean annual 1.8 hospital days (adjusted difference, 0.0; 95% CI, -0.3 to 0.3; P = .95). Surgery patients had a mean annual 1.3 nonprimary care outpatient visits during the years 2 through 6 vs 1.1 among the controls (adjusted difference, 0.3; 95% CI, 0.1 to 0.4; P = .003), but from year 7, the 2 groups did not differ (1.8 vs 1.9 mean annual visits; adjusted difference, -0.2; 95% CI, -0.4 to 0.1; P = .12). From year 7 to 20, the surgery group incurred a mean annual drug cost of US $930; the control patients, $1123 (adjusted difference, -$228; 95% CI, -$335 to -$121; P < .001).Compared with controls, surgically treated patients used more inpatient and nonprimary outpatient care during the first 6-year period after undergoing bariatric surgery but not thereafter. Drug costs from years 7 through 20 were lower for surgery patients than for control patients.clinicaltrials.gov Identifier: NCT01479452.

Increased sensitivity to alcohol after gastric bypass has been described. The aim of this study was to investigate whether bariatric surgery is associated with alcohol problems.The prospective, controlled Swedish Obese Subjects (SOS) study enrolled 2,010 obese patients who underwent bariatric surgery (68% vertical banded gastroplasty (VBG), 19% banding, and 13% gastric bypass) and 2,037 matched controls. Patients were recruited between 1987 and 2001. Data on alcohol abuse diagnoses, self-reported alcohol consumption, and alcohol problems were obtained from the National Patient Register and questionnaires. Follow-up time was 8-22 years.During follow-up, 93.1% of the surgery patients and 96.0% of the controls reported alcohol consumption classified as low risk by the World Health Organization (WHO). However, compared to controls, the gastric bypass group had increased risk of alcohol abuse diagnoses (adjusted hazard ratio [adjHR] = 4.97), alcohol consumption at least at the WHO medium risk level (adjHR = 2.69), and alcohol problems (adjHR = 5.91). VBG increased the risk of these conditions with adjHRs of 2.23, 1.52, and 2.30, respectively, while banding was not different from controls.Alcohol consumption, alcohol problems, and alcohol abuse are increased after gastric bypass and VBG.

Abstract In idiopathic thrombocytopenic purpura (ITP), platelets are destroyed in the spleen, liver, and bone marrow (BM) by autoantibodies and cytotoxic T cells. In a DNA microarray screen of peripheral blood T cells, we found that VLA-4, CX3CR1, and CXCR4, involved in T-cell homing, had increased expression in ITP patients compared with controls. However, we only found increased protein expression of VLA-4 on T cells from peripheral blood by flow cytometry. To address a possible recruitment of T cells into the organs involved in platelet destruction, we analyzed T cells in BM. In BM, T-cell surface expression of VLA-4 and CX3CR1 was increased in ITP patients compared with controls. Furthermore, the number of CD3+ T cells in BM, but not in blood, was increased in ITP patients compared with controls. This finding was confirmed by immunohistochemistry of BM biopsies. The number of regulatory T cells (CD4+/CD25bright) was decreased in the BM of ITP patients, whereas Fas expression was increased. In conclusion, ITP is associated with accumulation and activation of T cells in the BM. Recruitment of T cells into the target organ (eg, BM) is plausible and may be facilitated through increased VLA-4 and CX3CR1 expression. These molecules might serve as new treatment targets in ITP.

Background Bariatric surgery is associated with remission of diabetes and prevention of diabetic complications in patients with obesity and type 2 diabetes. Long-term effects of bariatric surgery on microvascular complications in patients with prediabetes are unknown. The aim of this study was to examine the effects of bariatric surgery on incidence of microvascular complications in patients with obesity stratified by baseline glycaemic status. Methods Patients were recruited to the Swedish Obese Subjects (SOS) study between Sept 1, 1987, and Jan 31, 2001. Inclusion criteria were age 37–60 years and BMI of 34 kg/m2 or greater in men and 38 kg/m2 or greater in women. Exclusion criteria were identical in surgery and control groups and designed to exclude patients not suitable for surgery. The surgery group (n=2010) underwent gastric bypass (265 [13%]), gastric banding (376 [19%]), or vertical-banded gastroplasty (1369 [68%]). Participants in the control group (n=2037) received usual care. Bodyweight was measured and questionnaires were completed at baseline and at 0·5 years, 1 year, 2 years, 3 years, 4 years, 6 years, 8 years, 10 years, 15 years, and 20 years. Biochemical variables were measured at baseline and at 2 years, 10 years, and 15 years. We categorised participants into subgroups on the basis of baseline glycaemic status (normal [fasting blood glucose concentration <5·0 mmol/L], prediabetes [5·0–6·0 mmol/L], screen-detected diabetes [≥6·1 mmol/L at baseline visit without previous diagnosis], and established diabetes [diagnosis of diabetes before study inclusion]). We obtained data about first incidence of microvascular disease from nationwide registers and about diabetes incidence at study visits at 2 years, 10 years, and 15 years. We did the main analysis by intention to treat, and subgroup analyses after stratification by baseline glycaemic status and by diabetes status at the 15 year follow-up. The SOS study is registered with ClinicalTrials.gov, NCT01479452. Findings 4032 of the 4047 participants in the SOS study were included in this analysis. We excluded four patients with suspected type 1 diabetes, and 11 patients with unknown glycaemic status at baseline. At baseline, 2838 patients had normal blood glucose, 591 had prediabetes, 246 had screen-detected diabetes, and 357 had established diabetes. Median follow-up was 19 years (IQR 16–21). We identified 374 incident cases of microvascular disease in the control group and 224 in the surgery group (hazard ratio [HR] 0·56, 95% CI 0·48–0·66; p<0·0001). Interaction between baseline glycaemic status and effect of treatment on incidence of microvascular disease was significant (p=0·0003). Unadjusted HRs were lowest in the subgroup with prediabetes (0·18, 95% CI 0·11–0·30), followed by subgroups with screen-detected diabetes (0·39, 0·24–0·65), established diabetes (0·54, 0·40–0·72), and normoglycaemia (0·63, 0·48–0·81). Surgery was associated with reduced incidence of microvascular events in people with prediabetes regardless of whether they developed diabetes during follow-up. Interpretation Bariatric surgery was associated with reduced risk of microvascular complications in all subgroups, but the greatest relative risk reduction was observed in patients with prediabetes at baseline. Our results suggest that prediabetes should be treated aggressively to prevent future microvascular events, and effective non-surgical treatments need to be developed for this purpose. Funding US National Institutes of Health, Swedish Research Council, Sahlgrenska University Hospital Regional Agreement on Medical Education and Research, and Swedish Diabetes Foundation.

To examine the long-term effects of bariatric surgery on female-specific cancer in women with obesity.The prospective, matched Swedish Obese Subjects (SOS) study was designed to examine outcomes after bariatric surgery. This study includes 1420 women from the SOS cohort that underwent bariatric surgery and 1447 contemporaneously matched controls who received conventional obesity treatment. Age was 37-60years and BMI was ≥38kg/m2. Information on cancer events was obtained from the Swedish National Cancer Registry. Median follow-up time was 18.1years (interquartile range 14.8-20.9years, maximum 26years). This study is registered with ClinicalTrials.gov, NCT01479452.Bariatric surgery was associated with reduced risk of overall cancer (hazard ratio=0.71; 95% CI 0.59-0.85; p<0.001). About half of the observed cancers were female-specific, and the incidence of these were lower in the surgery group compared with the control group (hazard ratio=0.68; 95% CI 0.52-0·88; p=0.004). The surgical treatment benefit with respect to female-specific cancer was significantly associated with baseline serum insulin (interaction p value=0.022), with greater relative treatment benefit in patients with medium or high insulin levels. Separate analyses of different types of female-specific cancers showed that bariatric surgery was associated with reduced risk of endometrial cancer (hazard ratio=0.56: 95% CI 0.35-0.89; p=0.014).In this long-term study, bariatric surgery was associated with reduced risk of female-specific cancer, especially in women with hyperinsulinemia at baseline.This project was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK105948 (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health), the Swedish Research Council K2013-99X-22279-01, K2013-54X-11285-19, Sahlgrenska University Hospital ALF research grant and Swedish Diabetes Foundation.

Men and women differ in body fat distribution and adipose tissue metabolism as well as in obesity comorbidities and their response to obesity treatment.The objective of the study was a search for sex differences in adipose tissue function.This was an exploratory study performed at a university hospital.Resting metabolic rate (RMR), body composition, and sc adipose tissue genome-wide expression were measured in the SOS Sib Pair study (n = 732).The relative contribution of fat mass to RMR and the metabolic rate per kilogram adipose tissue was higher in women than in men (P value for sex by fat mass interaction = .0019). Women had increased expression of genes involved in mitochondrial function, here referred to as a mitochondrial gene signature. Analysis of liver, muscle, and blood showed that the pronounced mitochondrial gene signature in women was specific for adipose tissue. Brown adipocytes are dense in mitochondria, and the expression of the brown adipocyte marker uncoupling protein 1 was 5-fold higher in women compared with men in the SOS Sib Pair Study (P = 7.43 × 10(-7)), and this was confirmed in a cross-sectional, population-based study (n = 83, 6-fold higher in women, P = .00256).The increased expression of the brown adipocyte marker uncoupling protein 1 in women indicates that the higher relative contribution of the fat mass to RMR in women is in part explained by an increased number of brown adipocytes.

Bariatric surgery is an established treatment for obesity, but knowledge on the long-term incidence of revisional surgery is scarce.To determine the incidence and type of revisional surgery after bariatric surgery in 26 years of follow-up of participants in the Swedish Obese Subjects (SOS) study.The SOS study is a prospective nonrandomized controlled study comparing bariatric surgery (banding, vertical banded gastroplasty [VBG], and gastric bypass [GBP]) with usual care. The bariatric surgeries in the SOS study were conducted at 25 public surgical departments in Sweden. Men with body mass index values of 34 or higher and women with body mass indexes of 38 or higher were recruited to the surgery group of the SOS study between September 1, 1987, and January 31, 2001, and follow-up continued until December 31, 2014. Data analysis occurred from November 2016 to April 2018.Banding, VBG, or GBP.Revisional surgeries, analyzed using data from questionnaires, hospital records, and the Swedish National Patient register through December 31, 2014.A total of 2010 participants underwent surgery. The age range was 37 to 60 years. A total of 376 participants underwent banding (18.7%), while 1365 had VBG (67.9%) and 266 had GBP (13.2%). During a median follow-up of 19 years, 559 participants (27.8%) underwent first-time revisional surgery, including 354 conversions to other bariatric procedures (17.6%), 114 corrective surgeries (5.6%), and 91 reversals to normal anatomy (4.5%). Revisional surgeries (conversions, corrective surgery, and reversals) were common after banding (153 of 376 [40.7%]) and VBG (386 of 1365 [28.3%]) but relatively rare after GBP (20 of 266 [7.5%]). Patients who had banding and VBG primarily underwent conversions to GBP or reversals. Incidence of reversals was 5 times higher after banding than after VBG (40.7% vs 7.5%; unadjusted hazard ratio, 5.19 [95% CI, 3.43-7.87]; P < .001). Corrective surgeries were equally common irrespective of the index surgery (72 of 1365 patients who had VBG [5.3%]; 23 of 376 patients who had banding [6.1%]; 19 of 266 patients who had GBP [7.1%]). Revisional surgery indications, including inadequate weight loss, band-associated complications (migration, stenosis, and slippage), staple-line disruptions, and postsurgical morbidity, varied depending on index surgery subgroup. Most corrections occurred within the first 10 years, whereas conversions and reversals occurred over the entire follow-up period.Corrective surgeries occur mainly within the first 10 years and with similar incidences across all 3 surgical subgroups, but indications varied. Conversions (mainly to GBP) and reversals occurred after many years and were most frequent after banding and VBG, reflecting a higher overall revisional surgery demand after these operations.

BackgroundHaematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years.MethodsClonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care.FindingsIn this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range −4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = −0.68, 1.74 E−04).InterpretationLow HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.FundingThe Swedish Research Council, The Swedish state under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, The Swedish Heart-Lung Foundation, The Novo Nordisk Foundation, The European Research Council, The Netherlands Organisation for Scientific Research.

To identify genes predominantly expressed in omental adipocytes, microarray expression profiles from 33 human tissues or cell types were analyzed, using an algorithm developed for identification of transcripts predominantly expressed in a certain tissue. Both known adipocyte-specific and more unexpected genes were among the 28 genes identified. To validate the approach, adipocyte expression of three of these genes, acute-phase serum amyloid A (A-SAA), aquaporin 7, and transport secretion protein-2.2, was compared with 17 other human tissues by real-time PCR. The unexpectedly high expression of A-SAA in adipocytes was further verified by Northern blot and immunohistochemistry. The liver, reported to be the main production site for A-SAA, displayed the second highest expression using microarray and real-time PCR. In obese subjects, adipose tissue mRNA and serum A-SAA levels were down-regulated during an 18-wk diet regime (P < 0.05 and P < 0.0001, respectively). A-SAA serum levels were highly correlated to adipose tissue mRNA levels (P < 0.001) and to the total (P < 0.0001) and sc (P < 0.0001) adipose tissue areas, as analyzed by computed tomography. We show that adipose tissue is a major expression site of A-SAA during the nonacute-phase reaction condition. This provides a direct link between adipose tissue mass and a marker for low-grade inflammation and cardiovascular risk.

Leptin affects body weight and reproduction mainly via receptors in the central nervous system. Different isoforms of the leptin receptor (leptin-R) exist, including a long isoform (leptin-R&lt;sub&gt;L&lt;/sub&gt;) with signalling capacity and short isoforms (leptin-R&lt;sub&gt;S&lt;/sub&gt;) with unknown function. The aim of this study was to examine leptin-R gene expression in different regions of the brain under conditions with altered body weight, in the female rat, including ovariectomy (OVX), oestradiol (E&lt;sub&gt;2&lt;/sub&gt;) treatment, fasting and a genetic model of obesity (Zucker &lt;i&gt;fa/fa&lt;/i&gt;). Leptin-R gene expression was analysed by in situ hybridization using probes recognizing all receptor isoforms (leptin-R) or specifically leptin-R&lt;sub&gt;L&lt;/sub&gt;. Transcripts recognized by the leptin-R probe were abundant in the choroid plexus (CP), arcuate nucleus (ARC), ventromedial nucleus (VMN), thalamus (TH) and piriform cortex (PC). Leptin-R&lt;sub&gt;L&lt;/sub&gt; transcripts were detected in the ARC, VMN, TH and PC but not in the CP. Although no sex difference was observed, leptin-R gene expression was reduced by E&lt;sub&gt;2&lt;/sub&gt; administration and increased by OVX. Administration of E&lt;sub&gt;2&lt;/sub&gt; reduced leptin-R&lt;sub&gt;L&lt;/sub&gt; gene expression in the ARC and VMN but did not alter the expression in the TH or PC. OVX had no effect on the expression of leptin-R&lt;sub&gt;L&lt;/sub&gt; mRNA. Fasting also caused a differential regulation of leptin-R mRNAs, with an increase in abundance of leptin-R&lt;sub&gt;L&lt;/sub&gt; transcripts in the TH despite a decrease in leptin-R in this area. Obese Zucker rats had a similar pattern of expression with an increased expression of leptin-R&lt;sub&gt;L&lt;/sub&gt; transcripts in all brain areas analysed and a decrease in leptin-R gene expression. These results demonstrate a differential regulation of leptin-R&lt;sub&gt;L&lt;/sub&gt; and leptin-R&lt;sub&gt;S&lt;/sub&gt; which could provide a mechanism for regulating access to, and sensitivity of, discrete regions of the brain for circulating leptin. We suggest that fasting and E&lt;sub&gt;2&lt;/sub&gt; alter the balance between leptin-R&lt;sub&gt;L&lt;/sub&gt; and leptin-R&lt;sub&gt;S&lt;/sub&gt; and that this could increase tissue sensitivity to leptin.

An automatic method for repetitive microsampling of blood from conscious animals was used to obtain detailed GH secretory profiles from normal female rats, which were compared with those in males and ovariectomized females. Female rats showed a highly variable GH secretory pattern, with sustained periods of low, almost continuous secretion, followed by very rapid bursts of high amplitude and short duration, occurring mostly at night. There was no clear relationship between the pattern of GH secretion and the phase of the oestrous cycle in rats continuously sampled over a 5-day period. In ovariectomized rats, the day:night difference was maintained, though the nocturnal GH surges were larger and of longer duration than in intact females. Male rats produced multicomponent GH bursts which continued unchanged throughout the day and night. This study shows for the first time that female rats switch to a rapid, highly pulsatile pattern of GH release at night, which can only be resolved by rapid blood sampling over extended periods in conscious undisturbed animals.

To determine whether some patients with idiopathic short stature have partial resistance to growth hormone (GH). Patients with idiopathic short stature have decreased serum levels of the GH receptor-related GH-binding protein (GHBP), and low GHBP levels are associated with complete GH insensitivity (Laron) syndrome. We hypothesized that patients with idiopathic short stature and low GHBP levels may also have a degree of GH insensitivity.Retrospective analysis of patients in a multicenter study.Ninety-six National Cooperative Growth Study centers in the United States and Canada.Five hundred eleven patients with idiopathic short stature who were treated with GH. All patients had a baseline height standard deviation score of less than -2 and a maximum stimulated GH level greater than 10 micrograms/L. Of these, 101 (20%) had a baseline GHBP standard deviation score of -2 or less.The patients with low GHBP levels, in comparison with those with normal GHBP levels, had a lower mean extracted standard deviation score for insulin-like growth factor I (-3.3 +/- 1.1 vs -2.5 +/- 1.4; p < 0.0001) but mean 12-hour GH values (2.8 +/- 1.1 vs 2.3 +/- 1.1 micrograms/L; p <0.0001). The differences between groups were statistically significant after control for age and weight-for-height standard deviation score. Among prepubertal patients, there was no significant difference between the low and normal GHBP groups in mean pretreatment or first-year growth rate (p = 0.74, 0.61 respectively) with comparable doses of GH.Patients with idiopathic short stature and low GHBP levels, compared with those with normal GHBP levels, had significantly lower standardized levels of insulin-like growth factor I, and higher mean 12-hour GH levels, which suggest partial GH insensitivity. There was no significant correlation of GHBP levels with the growth response to exogenous GH.

Abstract The growth hormone (GH) releasing ability of GH‐releasing factor (GRF) and a GH‐releasing hexapeptide, CHRP, have been studied in anaesthetized and conscious male and female rats. The GH responses to GHRP in anaesthetized rats were inconsistent, and this peptide was much less potent than GRF. Continuous iv infusions of GRF or GHRP both caused an initial GH release which was not maintained, and further GH release could be elicited by injection of GRF during an infusion of GHRP and vice versa. In contrast, conscious rats were much more sensitive to GHRP. Infusions of GHRP or GRF both caused an initial GH release. With GRF infusions, GH release continued in the normal episodic pattern whereas with GHRP infusion, GH secretion remained elevated over baseline and the normal pulsatile rhythm was disrupted. Plasma GH levels fell after stopping GHRP infusion, without an immediate resumption of normal GH pulsatility. Conscious male rats responded intermittently to injections of GRF given iv every 45 min, but when such serial injections of GRF were given during a continuous iv infusion of GHRP, the GH responses to GRF became regular and more uniform. These results suggest that GHRP prevents the normal cyclic refractoriness to GRF in male rats by disrupting cyclic somatostatin release. The greater potency of GHRP in conscious rats may also depend on the release of endogenous GRF since passive immunization with an anti‐GRF serum reduced the plasma GH response to GHRP infusion. Thus in the conscious animal, GHRP may release GH by complex actions at both a hypothalamic and pituitary level.

We have studied the rebound secretion of GH following short-term somatostatin (SS) infusions in conscious rats, using an automatic sampling system for withdrawing frequent microsamples of blood. Intravenous infusions of SS (5-50 micrograms/h per rat) inhibited spontaneous GH secretion, but when SS was withdrawn there was a large burst of rebound GH secretion. A sub-anaesthetic dose of urethane reduced such rebound bursts of GH, suggesting a hypothalamic involvement in rebound GH secretion. Passive immunization with an antibody against rat GH-releasing factor (GRF) attenuated the rebound GH secretory response to the withdrawal of an SS infusion (GH concentration during rebound secretion was 26 +/- 21 micrograms/l vs 475 +/- 127 micrograms/l (mean +/- S.E.M.), after 0.5 ml anti-GRF serum or non-immune serum respectively). The inhibition of GH rebound secretion was related to the dose of anti-GRF serum administered. Intravenous infusions of human GH (20-100 micrograms/h per rat) also reduced the size of the rebound GH secretion following SS withdrawal, in both male and female rats. We suggest that the rebound GH secretion that follows SS withdrawal in vivo is caused mainly by a hypothalamic release of GRF. Exogenous GH inhibits SS-induced rebound GH secretion in the conscious rat, possibly by inhibiting hypothalamic GRF release.

Background: Dry skin in atopic eczema depends on increased water loss. The mechanisms behind this are poorly understood. The aim of this work was to identify genes that may contribute to water loss in eczema. Methods: Affymetrix DNA microarrays U133A were used to analyse gene expression in skin biopsies from 10 patients with atopic eczema and 10 healthy controls. Results: DNA microarray analysis showed up‐regulation of 262 genes and down‐regulation of 129 genes in atopic eczema. The known functions of these genes were analysed using Gene Ontology to identify genes that could contribute to increased water loss. This led to identification of aquaporin 3 ( AQP3 ), which has a key role in hydrating healthy epidermis. Increased expression of AQP3 was found in eczema compared with healthy skin. This was confirmed with real‐time polymerase chain reaction ( P &lt; 0.001). In healthy skin, epidermal AQP3 immunoreactivity was weak and mainly found in the stratum basale. A gradient was formed with decreasing AQP3 staining in the lower layers of the stratum spinosum. By contrast, in acute and chronic atopic eczema strong AQP3 staining was found in both the stratum basale and the stratum spinosum. Conclusions: Aquaporin 3 is the predominant aquaporin in human skin. Increased expression and altered cellular distribution of AQP3 is found in eczema and this may contribute to water loss.

To test whether DNA sequence variation in 11 obesity genes is associated with maximum weight loss and weight regain over 6 years of follow-up in bariatric surgery patients of the Swedish obese subjects (SOS) intervention study.A total of 1443 subjects were available for analysis (vertical banded gastroplasty: n = 966, banding: n = 293 and gastric bypass: n = 184). Single-nucleotide polymorphisms (SNPs) from the following 11 genes were included: ADIPOQ, BDNF, FTO, GNB3, LEP, LEPR, MC4R, NR3C1, PPARG, PPARGC1A and TNF. General linear models were used to analyze associations between the SNPs and maximum weight loss and weight regain.The average maximum weight loss was 33.7 kg (s.d. 13.3; min -95.5 kg, max +2.0 kg), which was reached 2.2 (s.d. 1.6) years after the surgery. Subjects regained approximately 12 kg (range 0.0-51.4 kg) by year 6. After correcting for multiple testing, the FTO SNP rs16945088 remained significantly associated with maximum weight loss (P = 0.0002), as minor allele carriers lost approximately 3 kg less compared with common allele homozygotes. This association was particularly evident in the banding surgery patients (P < 0.0001), whereas no significant association was found in the gastric bypass subjects. No other SNPs were associated with maximum weight loss. Furthermore, no SNPs were significantly associated with weight regain.The FTO SNP rs16945088 was associated with maximum weight loss after banding surgery. We found no evidence that obesity-risk SNPs in FTO or other obesity candidate genes derived from genome-wide association studies are associated with maximum weight loss or weight regain over 6 years of follow-up in bariatric surgery patients. The potential role of other obesity genes remains to be investigated.

To compare two bariatric surgical principles with regard to effects on blood pressure and salt intake.In most patients bariatric surgery induces a sustained weight loss and a reduced cardiovascular risk profile but the long-term effect on blood pressure is uncertain.Cohort study with data from the prospective, controlled Swedish Obese Subjects (SOS) study involving 480 primary health care centres and 25 surgical departments in Sweden. Obese patients treated with non-surgical methods (Controls, n = 1636 and n = 1132 at 2 y and 10 y follow up, respectively) were compared to patients treated with gastric bypass (GBP, n = 245 and n = 277, respectively) or purely restrictive procedures (vertical banded gastroplasty or gastric banding; VBG/B, n = 1534 and n = 1064, respectively).At long-term follow-up (median 10 y) GBP was associated with lowered systolic (mean: -5.1 mm Hg) and diastolic pressure (-5.6 mmHg) differing significantly from both VBG/B (-1.5 and -2.1 mmHg, respectively; p<0.001) and Controls (+1.2 and -3.8 mmHg, respectively; p<0.01). Diurnal urinary output was +100 ml (P<0.05) and +170 ml (P<0.001) higher in GBP subjects than in weight-loss matched VBG/B subjects at the 2 y and 10 y follow-ups, respectively. Urinary output was linearly associated with blood pressure only after GBP and these patients consumed approximately 1 g salt per day more at the follow-ups than did VBG/B (P<0.01).The purely restrictive techniques VBG/B exerted a transient blood pressure lowering effect, whereas gastric bypass was associated with a sustained blood pressure reduction and an increased diuresis. The daily salt consumption was higher after gastric bypass than after restrictive bariatric surgery.

Context: Cell death-inducing DNA fragmentation factor-α-like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings that CIDEA inhibits the brown adipose tissue uncoupling process in rodents.

Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity.PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction = 0.002). This provides evidence for the obesity interaction with I48M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study.Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.

Obesity is associated with elevated serum transaminase levels and non-alcoholic fatty liver disease and weight loss is a recommended therapeutic strategy. Bariatric surgery is effective in obtaining and maintaining weight loss. Aim of the present study was to examine the long-term effects of bariatric surgery on transaminase levels in obese individuals.The Swedish Obese Subjects (SOS) study is a prospective controlled intervention study designed to compare the long-term effects of bariatric surgery and usual care in obese subjects. A total of 3,570 obese participants with no excess of alcohol consumption at baseline (1,795 and 1,775 in the control and surgery group, respectively) were included in the analyses. Changes in transaminase levels during follow-up were compared in the surgery and control groups.Compared to usual care, bariatric surgery was associated with lower serum ALT and AST levels at 2- and 10- year follow up. The reduction in ALT levels was proportional to the degree of weight loss. Both the incidence of and the remission from high transaminase levels were more favorable in the surgery group compared to the control group. Similarly, the prevalence of ALT/AST ratio <1 was lower in the surgery compared to the control group at both 2- and 10-year follow up.Bariatric surgery results in a sustained reduction in transaminase levels and a long-term benefit in obese individuals.

The aim of this work was to analyse the rates of incidence and remission of type 2 diabetes in relation to baseline BMI and weight change in the prospective, controlled Swedish Obese Subjects (SOS) study. Three-thousand four-hundred and eighty-five obese individuals receiving bariatric surgery or conventional treatment were grouped into four baseline BMI categories (<35, 35–40, 40–45 or ≥45 kg/m2) and five weight-change categories according to their BMI at 2 years (increase [≥1 BMI unit increase], no change [less than 1 BMI unit change], minor reduction [−1 to −9 BMI units], medium reduction [−10 to −14 BMI units] and major reduction [< −15 BMI units]). The incidence and remission of diabetes at 2 years was assessed. Among individuals with no weight change, diabetes incidence rates were 5.5%, 7.4%, 8.3% and 5.2%, in the four baseline BMI categories, respectively. In those with an initial BMI of 35–40, 40–45 and ≥45 kg/m2 who attained a minor reduction in weight, the corresponding rates were 1.3%, 1.2% and 3.4%, respectively. In both the medium- and major-weight-reduction groups, diabetes incidence was ≤0.5%. Among individuals with diabetes at baseline, the remission rates were 15.3–26.9% in the no-weight-change groups, and 48.1–70% for individuals who attained a minor weight reduction. In the medium- and major-weight-reduction groups, the remission rate was 77–97%. There were no differences in 2 year incidence and remission rates between different baseline BMI groups that achieved the same degree of weight reduction. In obese individuals, the favourable effect of weight reduction on type 2 diabetes incidence and remission is independent of initial BMI. Trial registration ClinicalTrials.gov number NCT01479452

Patients with a BMI <35 kg/m(2) and patients with a BMI between 35 and 40 kg/m(2) without comorbidities are noneligible by current eligibility criteria for bariatric surgery. We used Swedish obese subjects (SOS) to explore long-term outcomes in noneligible versus eligible patients.The SOS study involved 2,010 obese patients who underwent bariatric surgery (68% vertical-banded gastroplasty, 19% banding, and 13% gastric bypass) and 2,037 contemporaneously matched obese controls receiving usual care. At inclusion, the participant age was 37-60 years and BMI was ≥34 kg/m(2) in men and ≥38 kg/m(2) in women. The effect of surgery was assessed in patients that do (n = 3,814) and do not (n = 233) meet current eligibility criteria. The date of analysis was 1 January 2012. The follow-up time was up to 20 years, with a median of 10 years.Cardiovascular risk factors were significantly improved both in noneligible and eligible individuals after 10 years of follow-up. Surgery reduced the diabetes incidence in both the noneligible (adjusted hazard ratio 0.33 [95% CI 0.13-0.82], P = 0.017) and eligible (0.27 [0.22-0.33], P < 0.001) groups. We could not detect a difference in the effect of surgery between the groups (adjusted interaction P value = 0.713).Bariatric surgery drastically reduced the incidence of type 2 diabetes both in noneligible and eligible patients and improved cardiovascular risk factors in both groups. Our results show that strict BMI cutoffs are of limited use for bariatric surgery prioritization if the aim is to prevent diabetes and improve cardiovascular risk factors.

Recent studies have reported associations of sirtuin 1 ( SIRT1 ) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case‐control analyses were performed using 1,533 obese subjects (896 adults, BMI &gt;40 kg/m 2 and 637 children, BMI &gt;97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r 2 = 0.96) were significantly associated with adult obesity, rs33957861 ( P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61–0.92) and rs11599176 ( P value: 0.006, OR = 0.74, CI = 0.61–0.90). Expression of SIRT1 mRNA was measured in BMI‐discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings ( r 2 = 0.13, P value = 3.36 × 10 −7 ) and lower SIRT1 expression was associated with obesity ( P value = 1.56 × 10 −35 ). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI ( P values: 4 × 10 −4 , 6 × 10 −4 , 4 × 10 −4 , and 2 × 10 −3 ) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.

Background: There is a need for a better understanding of the factors that influence long-term weight outcomes after bariatric surgery. Objective: We examined whether pretreatment and posttreatment levels of cognitive restraint, disinhibition, and hunger and 1-y changes in these eating behaviors predict short- and long-term weight changes after surgical and conventional treatments of severe obesity. Design: Participants were from an ongoing, matched (nonrandomized) prospective intervention trial of the Swedish Obese Subjects (SOS) study. The current analyses included 2010 obese subjects who underwent bariatric surgery and 1916 contemporaneously matched obese controls who received conventional treatment. Physical measurements (e.g., weight and height) and questionnaires (e.g., Three-Factor Eating Questionnaire) were completed before the intervention and 0.5, 1, 2, 3, 4, 6, 8, and 10 y after the start of the treatment. Structural equation modeling was used as the main analytic strategy. Results: The surgery group lost more weight and reported greater decreases in disinhibition and hunger at 1- and 10-y follow-ups (all P < 0.001 in both sexes) than the control group did. Pretreatment eating behaviors were unrelated to subsequent weight changes in surgically treated patients. However, patients who had lower levels of 6-mo and 1-y disinhibition and hunger (β = 0.13–0.29, P < 0.01 in men; β = 0.11–0.28, P < 0.001 in women) and experienced larger 1-y decreases in these behaviors (β = 0.31–0.48, P < 0.001 in men; β = 0.24–0.51, P < 0.001 in women) lost more weight 2, 6, and 10 y after surgery. In control patients, larger 1-y increases in cognitive restraint predicted a greater 2-y weight loss in both sexes. Conclusion: A higher tendency to eat in response to various internal and external cues shortly after surgery predicted less-successful short- and long-term weight outcomes, making postoperative susceptibility for uncontrolled eating an important indicator of targeted interventions. This trial was registered at clinicaltrials.gov as NCT01479452.

Bariatric surgery prevents and induces remission of type 2 diabetes in many patients. The effect of preoperative glucose status on long-term health-care costs is unknown. We aimed to assess health-care costs over 15 years for patients with obesity treated conventionally or with bariatric surgery and who had either euglycaemia, prediabetes, or type 2 diabetes before intervention.The Swedish Obese Subjects (SOS) study is a prospective study of adults who had bariatric surgery and contemporaneously matched controls who were treated conventionally (age 37-60 years; BMI of ≥34 in men and ≥38 in women) recruited from 25 Swedish surgical departments and 480 primary health-care centres. Exclusion criteria were identical for both study groups, and were previous gastric or bariatric surgery, recent malignancy or myocardial infarction, selected psychiatric disorders, and other contraindicating disorders to bariatric surgery. Conventional treatment ranged from no treatment to lifestyle intervention and behaviour modification. In this study, we retrieved prescription drug costs for the patients in the SOS study via questionnaires and the nationwide Swedish Prescribed Drug Register. We retrieved data for inpatient and outpatient visits from the Swedish National Patient Register. We followed up the sample linked to register data for up to 15 years. We adjusted mean differences for baseline characteristics. Analyses were by intention to treat. The SOS study is registered with ClinicalTrials.gov, number NCT01479452.Between Sept 1, 1987, and Jan 31, 2001, 2010 adults who had bariatric surgery and 2037 who were treated conventionally were enrolled into the SOS study. In this study, we followed up 4030 patients (2836 who were euglycaemic; 591 who had prediabetes; 603 who had diabetes). Drug costs did not differ between the surgery and conventional treatment groups in the euglycaemic subgroup (surgery US$10,511 vs conventional treatment $10,680; adjusted mean difference -$225 [95% CI -2080 to 1631]; p=0·812), but were lower in the surgery group in the prediabetes ($10,194 vs $13,186; -$3329 [-5722 to -937]; p=0·007) and diabetes ($14,346 vs $19,511; -$5487 [-7925 to -3049]; p<0·0001) subgroups than in the conventional treatment group. Compared with the conventional treatment group, we noted greater inpatient costs in the surgery group for the euglycaemic ($51,225 vs $25,313; $22,931 [19,001-26,861]; p<0·0001), prediabetes ($58,699 vs $32,861; $27,152 [18,736-35,568]; p<0·0001), and diabetes ($61,569 vs $47,569; 18,697 [9992-27,402]; p<0·0001) subgroups. We noted no differences in outpatient costs. Total health-care costs were higher in the surgery group in the euglycaemic ($71,059 vs $45,542; $22,390 [17,358-27,423]; p<0·0001) and prediabetes ($78,151 vs $54,864; $26,292 [16,738-35,845]; p<0·0001) subgroups than in the conventional treatment group, whereas we detected no difference between treatment groups in patients with diabetes ($88,572 vs $79,967; $9081 [-1419 to 19,581]; p=0·090).Total health-care costs were higher for patients with euglycaemia or prediabetes in the surgery group than in the conventional treatment group, but we detected no difference between the surgery and conventional treatment groups for patients with diabetes. Long-term health-care cost results support prioritisation of patients with obesity and type 2 diabetes for bariatric surgery.AFA Försäkring and Swedish Scientific Research Council.

Background: Approximately 20-30% of obese patients do not achieve successful weight outcomes after bariatric surgery.Objective: We examined whether short-term changes (≤0.5 y postsurgery) in energy intake and macronutrient composition after bariatric surgery could predict 10-y weight change.Design: Participants were recruited from the Swedish Obese Subjects (SOS) study, which was a matched (nonrandomized) prospective trial that compared bariatric surgery with usual care for obese patients. A total of 2010 patients who underwent bariatric surgery were included in the study. Physical examinations (e.g., weight) and questionnaires (e.g., dietary questionnaire) were completed before and 0.5, 1, 2, 3, 4, 6, 8, and 10 y after surgery. For the main analytic strategy, a linear mixed model was implemented, which included repeated measures with a random intercept and an unstructured covariance matrix.Results: Short-term changes in energy intake (P < 0.001) and in relative proportions of energy from carbohydrates (P < 0.001), fat (P < 0.001), and protein (P < 0.05) were associated with 10-y weight change after bariatric surgery. At the 10-y follow-up, men and women with the largest reductions in energy intake had lost 7.3% and 3.9% more weight, respectively, compared with that of subjects with the smallest intake reductions (P < 0.001). Greater weight loss was achieved in men and women who favored protein and carbohydrates over fat and in subjects who favored protein over carbohydrates than in individuals who favored the opposite changes in macronutrient composition (P < 0.05).Conclusions: The level of energy restriction that is achieved at 0.5 y after bariatric surgery predicts long-term weight loss. Weight loss is also associated with a changing dietary macronutrient composition. This trial was registered at clinicaltrials.gov as NCT01479452.

Obesity is a major public health problem leading to co-morbidities such as diabetes, hypertension and kidney failure. Bariatric surgery results in pronounced and maintained weight loss and prevention of obesity-related diseases and their complications. Most studies of bariatric surgery on kidney disease show improvements after surgery. However, long-term studies analyzing hard end-points are lacking. Here we report on the long-term effects of bariatric surgery compared to usual obesity care on incidence of end-stage renal disease (ESRD) alone and in combination with chronic kidney disease stage 4 (CKD4/ESRD). 4047 patients were included in the Swedish Obese Subjects (SOS) study. Inclusion criteria were age 37–60 years and BMI ≥ 34 in men and BMI ≥ 38 in women. Patients in the bariatric surgery group (N = 2010) underwent banding (18%), vertical banded gastroplasty (69%), or gastric bypass (13%); controls (N = 2037) received usual obesity care. In this analysis, patients were followed up for a median time of 18 years. The incidence of ESRD and CKD4 was obtained by crosschecking the SOS database with the Swedish National Patient Register. During follow-up, ESRD occurred in 13 patients in the surgery group and in 26 patients in the control group (adjusted hazard ratio (HR) = 0.27; 95% CI 0.12–0.60; p = 0.001). The number of CKD4/ESRD events was 23 in the surgery group and 39 in the control group (adjusted HR = 0.33; 95% CI 0.18–0.62; p < 0.001). In both analyses, bariatric surgery had a more favorable effect in patients with baseline serum insulin levels above median compared to those with lower insulin levels (interaction p = 0.010). Treatment benefit of bariatric surgery was also greater in patients with macroalbuminuria at baseline compared to those without macroalbuminuria (interaction p < 0.001). Our study showed for the first time that bariatric surgery is associated with a long-term protection against ESRD and CKD4/ESRD.

OBJECTIVE It has been suggested that weight change–independent effects on fasting insulin and glucose levels are present after gastric bypass (GBP) but not after banding and vertical banded gastroplasty (VBG). We therefore evaluated weight change–adjusted effects of GBP, compared with restrictive surgical procedures, on long-term changes in fasting levels of glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the Swedish Obese Subjects (SOS) study. RESEARCH DESIGN AND METHODS Participants who completed the 2-year (n = 1,762) and/or the 10-year (n = 1,216) follow-up were divided into three weight change classes (weight loss &amp;gt;30%, 20–30%, or ≤20%), and by surgical method (banding, VBG, or GBP). Glucose, insulin, and HOMA-IR changes were analyzed in relation to weight change over 2 and 10 years. Analyses were performed in the full cohort and also in subgroups based on baseline glucose status. RESULTS Within weight change classes, reductions in glucose, insulin, and HOMA-IR were similar in the three surgery groups both at 2 and at 10 years. Reductions in glucose, insulin, and HOMA-IR increased with increasing weight loss, and changes were typically related to weight change within each surgery group. Moreover, the association between weight change and change in glucose, insulin, or HOMA-IR did not differ between the surgery groups at 2 and 10 years. When patients were subdivided also by baseline glucose status, similar relationships between weight changes and changes in glucose, insulin, and HOMA-IR were observed. CONCLUSIONS Even though weight loss–independent effects are important for short-term diabetes remission, our results suggest that degree of weight loss is more important for long-term reductions in fasting insulin and glucose than choice of bariatric surgery procedure.

Objectives To assess the long-term effect of bariatric surgery on the incidence of gout and hyperuricaemia in participants of the Swedish Obese Subjects (SOS) study. Methods This report includes 1982 subjects who underwent bariatric surgery and 1999 obese controls from the SOS study, a prospective intervention trial designed to assess the effect of bariatric surgery compared with conventional treatment. None of the subjects had gout at baseline. An endpoint on gout incidence was created based on information on gout diagnosis and use of gout medications through national registers and questionnaires. Median follow-up for the incidence of gout was about 19 years for both groups. Moreover, the incidence of hyperuricaemia over up to 20 years was examined in a subgroup of participants having baseline uric acid levels &lt;6.8 mg/dL. Results Bariatric surgery was associated with a reduced incidence of gout compared with usual care (adjusted HR 0.60, 95% CI 0.48 to 0.75, p&lt;0.001). The difference in absolute risk between groups was 3 percentage points at 15 years, and the number of subjects needed to be treated by bariatric surgery to prevent one incident gout event was 32 (95% CI 22 to 59). The effect of bariatric surgery on gout incidence was not influenced by baseline risk factors, including body mass index. During follow-up, the surgery group had a lower incidence of hyperuricaemia (adjusted HR 0.47, 95% CI 0.39 to 0.58, p&lt;0.001). The difference in absolute risk between groups was 12 percentage points at 15 years, and the number of participants needed to be treated by bariatric surgery to prevent hyperuricaemia was 8 (95% CI 6 to 13). Conclusions Bariatric surgery prevents gout and hyperuricaemia in obese subjects. Trial registration number NCT01479452 ; Results.

Abstract Background Previous studies have reported an increased fracture risk after bariatric surgery. Objective To investigate the association between different bariatric surgery procedures and fracture risk. Methods Incidence rates and hazard ratios for fracture events were analysed in the Swedish Obese Subjects study; an ongoing, nonrandomized, prospective, controlled intervention study. Hazard ratios were adjusted for risk factors for osteoporosis and year of inclusion. Information on fracture events were captured from the Swedish National Patient Register. The current analysis includes 2007 patients treated with bariatric surgery (13.3% gastric bypass, 18.7% gastric banding, and 68.0% vertical banded gastroplasty) and 2040 control patients with obesity matched on group level based on 18 variables. Median follow‐up was between 15.1 and 17.9 years for the different treatment groups. Results During follow‐up, the highest incidence rate for first‐time fracture was observed in the gastric bypass group (22.9 per 1000 person‐years). The corresponding incidence rates were 10.4, 10.7 and 9.3 per 1000 person‐years for the vertical banded gastroplasty, gastric banding and control groups, respectively. The risk of fracture was increased in the gastric bypass group compared with the control group (adjusted hazard ratio [adjHR] 2.58; 95% confidence interval [CI] 2.02–3.31; P &lt; 0.001), the gastric banding group (adjHR 1.99; 95%CI 1.41–2.82; P &lt; 0.001), and the vertical banded gastroplasty group (adjHR 2.15; 95% CI 1.66–2.79; P &lt; 0.001). Conclusions The risk of fracture is increased after gastric bypass surgery. Our findings highlight the need for long‐term follow‐up of bone health for patients undergoing this treatment.

Abstract Aims Obesity is associated with increased risk for heart failure. We analysed data from the Swedish Obese Subjects (SOS) study, a prospective matched cohort study, to investigate whether bariatric surgery reduces this risk. Methods and results From the total SOS population (n = 4047), we identified 4033 obese individuals with no history of heart failure at baseline, of whom 2003 underwent bariatric surgery (surgery group) and 2030 received usual care (control group). First-time principal diagnoses of heart failure were identified by crosschecking the SOS database with the Swedish National Patient Register and the Swedish Cause of Death Register using diagnosis codes. During a median follow-up of 22 years, first-time heart failure occurred in 188 of the participants treated with surgery and in 266 of those receiving usual care. The risk of developing heart failure was lower in the surgery group than in the control group [sub-hazard ratio 0.65, 95% confidence interval (CI) 0.54–0.79; P &amp;lt; 0.001]. After pooling data from the two study groups, the quartile of subjects with the largest weight loss after 1 year (mean −41 kg) displayed the greatest risk reduction (sub-hazard ratio 0.51, 95% CI 0.30–0.70; P &amp;lt; 0.001). This association remained statistically significant after adjustment for surgical intervention and potential baseline confounders (sub-hazard ratio 0.60, 95% CI 0.36–0.97; P = 0.038). Conclusion Compared with usual care, bariatric surgery was associated with reduced risk of heart failure among persons being treated for obesity. The risk of heart failure appeared to decline in parallel with a greater degree of weight loss. ClinicalTrials.gov Identifier NCT01479452.

Obesity and type 2 diabetes are associated with serious adverse health effects, including cancer. Although bariatric surgery has been shown to reduce cancer risk in patients with obesity, the effect of bariatric surgery on cancer risk in patients with obesity and diabetes is less studied. We therefore examined the long-term incidence of cancer after bariatric surgery and usual care in patients with obesity and diabetes in the matched prospective Swedish Obese Subjects (SOS) study.The SOS study examines long-term outcomes following bariatric surgery or usual care. The current analysis includes 701 patients with obesity and type 2 diabetes at baseline, 393 of whom underwent bariatric surgery and 308 who received conventional obesity treatment. Information on cancer events was obtained from the Swedish National Cancer Register. Median follow-up time was 21.3 years (interquartile range 17.6-24.8 years, maximum 30.7 years).During follow-up, the incidence rate for first-time cancer was 9.1 per 1,000 person-years (95% CI 7.2-11.5) in patients with obesity and diabetes treated with bariatric surgery and 14.1 per 1,000 person-years (95% CI 11.2-17.7) in patients treated with usual obesity care (adjusted hazard ratio 0.63 [95% CI 0.44-0.89], P = 0.008). Moreover, surgery was associated with reduced cancer incidence in women (0.58 [0.38-0.90], P = 0.016), although the sex-treatment interaction was nonsignificant (P = 0.630). In addition, diabetes remission at the 10-year follow-up was associated with reduced cancer incidence (0.40 [0.22-0.74], P = 0.003).These results suggest that bariatric surgery prevents cancer in patients with obesity and diabetes and that durable diabetes remission is associated with reduced cancer risk.

Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery.In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI.10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m2 (95% CI 2·6-3·0) and mean RMSE BMI was 4·7 kg/m2 (4·4-5·0), and the mean difference between predicted and observed BMI was -0·3 kg/m2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery.We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions.SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).

Abstract The impact of the adoption of the new biosynthetic growth hormone (GH) WHO International Reference Preparation (IRP 88/624), and the recommendation to report results in μg/L instead of mU/L, is described. Conversion factors were determined by comparing both the linear and nonlinear relations of the GH values. The Pharmacia polyclonal IRMA (p-IRMA) and the DELFIA® monoclonal time-resolved immunofluorometric assay (trIFMA) with kit calibrators calibrated either against the pituitary-derived WHO IRP 80/505 or the new 88/624 were evaluated. Conversion factors of 4.17 mU/L = 1 μg/L for the p-IRMA and 4.31 mU/L = 1 μg/L for the trIFMA were necessary. Different cross-reactivity patterns for the deaminated and dimer 22-kDa, 20-kDa, and 17-kDa GH isoforms were found. Expected GH recovery was similar when the measured values were adjusted according to the results of the cross-reactivity study.

Circulating GH consists of multiple molecular isoforms, all derived from the one gene in nonpregnant humans. To assess the effect of a potent stimulus to pituitary secretion on GH isoforms, we studied 17 aerobically trained males (age, 26.9 ± 1.5 yr) in a randomized, repeat measures study of rest vs. exercise. Exercise consisted of continuous cycle ergometry at approximately 80% of predetermined maximal oxygen uptake for 20 min. Serum was assayed for total, pituitary, 22-kDa, recombinant, non-22-kDa, 20-kDa, and immunofunctional GH. All isoforms increased during, peaked at the end, and declined after exercise. At peak exercise, 22-kDa GH was the predominant isoform. After exercise, the ratios of non-22 kDa/total GH and 20-kDa GH/total GH increased and those of recombinant/pituitary GH decreased. The disappearance half-times for pituitary GH and 20-kDa GH were significantly longer than those for all other isoforms. We conclude that 1) all molecular isoforms of GH measured increased with and peaked at the end of acute exercise, with 22-kDa GH constituting the major isoform in serum during exercise; and 2) the proportion of non-22-kDa isoforms increased after exercise due in part to slower disappearance rates of 20-kDa and perhaps other non-22-kDa GH isoforms. It remains to be determined whether the various biological actions of different GH isoforms impact on postexercise homeostasis.

Objective— Macrophage-mediated oxidation of low-density lipoprotein (LDL) by enzymes, such as the lipoxygenases, is considered of major importance for the formation of oxidized LDL during atherogenesis. Macrophages have been identified in hypoxic areas in atherosclerotic plaques. Methods and Results— To investigate the role of hypoxia in macrophage-mediated LDL oxidation, we incubated human monocyte-derived macrophages with LDL under normoxic (21% O 2 ) or hypoxic (0% O 2 ) conditions. The results showed that hypoxic macrophages oxidized LDL to a significantly higher extent than normoxic cells. Interestingly, the mRNA and protein expression of 15-lipoxygenase-2 (15-LOX-2) as well as the activity of this enzyme are elevated in macrophages incubated at hypoxia. Both the unspliced 15-LOX-2 and the spliced variant 15-LOX-2sv-a are found in macrophages. In addition, 15-LOX-2 was identified in carotid plaques in some macrophage-rich areas but was only expressed at low levels in nondiseased arteries. Conclusions— In summary, these observations show for the first time that 15-LOX-2 is expressed in hypoxic macrophages and in atherosclerotic plaques and suggest that 15-LOX-2 may be one of the factors involved in macrophage-mediated LDL oxidation at hypoxia.

Context: CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism. Objective: The aim of the study was to test the hypothesis that adipose tissue C/EBPα regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPα and metabolic parameters. Design and Methods: Adipose tissue C/EBPα mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPα was used to identify genes regulated by C/EBPα in 3T3-L1 cells. Association between a genetic variation in C/EBPα (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4866). Results: During caloric restriction, adipose tissue C/EBPα mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPα regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-β dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPα mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041). Conclusions: Adipose tissue C/EBPα regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPα is associated with triglycerides in two independent populations.

&lt;i&gt;Background:&lt;/i&gt; Reference values are usually defined based on blood samples from healthy men or nonpregnant women in the age range of 20–50 years. These values are not optimal for elderly patients, as many biological markers change over time and adequate reference values are important for correct clinical decisions. &lt;i&gt;Objective:&lt;/i&gt; To validate NORIP (Nordic Reference Interval Project) reference values in a 70-year-old population. &lt;i&gt;Methods:&lt;/i&gt; We studied 27 frequently used laboratory tests. The 2.5th and 97.5th percentiles for these markers were calculated according to the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values. &lt;i&gt;Results:&lt;/i&gt; Reference values are reported for plasma alanine aminotransferase, albumin, alkaline phosphatase, pancreas amylase, apolipoprotein A1, apolipoprotein B, aspartate aminotransferase, bilirubin, calcium, chloride, cholesterol, creatinine, creatine kinase, C-reactive protein, glucose, γ-glutamyltransferase, HDL-cholesterol, iron, lactate dehydrogenase, LDL-cholesterol, magnesium, phosphate, potassium, sodium, transferrin, triglycerides, urate and urea. &lt;i&gt;Conclusion:&lt;/i&gt; Reference values calculated from the whole population and a subpopulation without cardiovascular disease showed strong concordance. Several of the reference interval limits were outside the 90% CI of a Scandinavian population (NORIP).

Human adipose tissue is a major site of expression of inhibin beta B (INHBB) which homodimerizes to form the novel adipokine activin B. Our aim was to determine if molecules needed for a local action of activin B are expressed in adipose tissue. Microarray analysis showed that adipose tissue expressed activin type I and II receptors and that the expression of activin receptor-like kinase 7 (ALK7) was adipose tissue specific. In obesity discordant siblings from the SOS Sib Pair study, adipose tissue ALK7 expression was higher in lean (n=90) compared to obese (n=90) subjects (p=4 x 10(-31)). Adipose tissue ALK7 expression correlated with several measures of body fat, carbohydrate metabolism and lipids. In addition, ALK7 and INHBB expression correlated but only in lean subjects and in subjects with normal glucose tolerance. We conclude that activin B may have local effects in adipose tissue and thereby influence obesity and its comorbidities.

The selenoprotein S (SELS) is a putative receptor for serum amyloid A, and recent studies have suggested that SELS may be a link between type 2 diabetes mellitus and inflammation. Genetic studies of SELS polymorphisms have revealed associations with circulating levels of inflammatory markers and hard end points of cardiovascular disease. In this study, we analyzed SELS expression in subcutaneous adipose tissue and SELS genotype in relation to metabolic risk factors. DNA microarray expression analysis was used to study the expression of SELS in lean and obese siblings from the Swedish Obese Subjects Sib Pair Study. TaqMan genotyping was used to analyze 3 polymorphisms, previously found to be associated with circulating levels of inflammatory markers, in the INTERGENE case-control study of myocardial infarction and unstable angina pectoris. Possible associations between SELS genotype and/or expression with anthropometry and measures of metabolic status were investigated. Real-time polymerase chain reaction was used to analyze the SELS expression in isolated human adipocytes incubated with insulin. In lean subjects, we found correlations between SELS gene expression in subcutaneous adipose tissue and measures of obesity (waist, P = .045; sagittal diameter, P = .031) and blood pressure (diastolic, P = .016; systolic P = .015); and in obese subjects, we found correlations with measures of obesity (body mass index, P = .03; sagittal diameter, P = .008) and glycemic control (homeostasis model assessment of insulin resistance, P = .011; insulin, P = .009) after adjusting for age and sex. The 5227GG genotype was associated with serum levels of insulin (P = .006) and homeostasis model assessment of insulin resistance (P = .007). The expression of SELS increased after insulin stimulation in isolated human adipocytes (P = .008). In this study, we found an association between both SELS gene expression in adipose tissue and SELS genotype with measures of glycemic control. In vitro studies demonstrated that the SELS gene is regulated by insulin in human subcutaneous adipocytes. This study further supports a role for SELS in the development of metabolic disease, especially in the context of insulin resistance.

MS is thought to be mediated by CD4(+) T-helper cells. To investigate the importance of CD8(+) cytotoxic T-cells in MS we analyzed peripheral blood T-cells by DNA microarray, and plasma and CSF levels of granzymes from MS patients and controls. Cytotoxic gene expression was decreased in peripheral T-cells from RRMS patients whereas plasma levels of granzymes were unchanged. However, granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission. Thus, CD8+ T-cell-mediated cytotoxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the immunopathogenesis of clinical relapses.

Using restriction fragment differential display (RFDD) technology, we have identified the imprinted gene neuronatin (Nnat) as a hypothalamic target under the influence of leptin. Nnat mRNA expression is decreased in several key appetite regulatory hypothalamic nuclei in rodents with impaired leptin signaling and during fasting conditions. Furthermore, peripheral administration of leptin to ob/ob mice normalizes hypothalamic Nnat expression. Comparative immunohistochemical analysis of human and rat hypothalami demonstrates that NNAT protein is present in anatomically equivalent nuclei, suggesting human physiological relevance of the gene product(s). A putative role of Nnat in human energy homeostasis is further emphasized by a consistent association between single nucleotide polymorphisms (SNPs) in the human Nnat gene and severe childhood and adult obesity.

Objective The longitudinal associations between a dietary pattern (DP) and cardiometabolic risk factors and cardiovascular disease (CVD) incidence were investigated in a cohort of adults with severe obesity. Methods The analysis included 2,037 individuals with severe obesity (>34 and >38 kg/m2 for men and women, respectively) from the Swedish Obese Subjects study repeatedly followed up for 10 years. Reduced rank regression was used to identify a DP characterized by dietary energy density, saturated fat intake, and fiber density. Mixed models examined relationships between repeated measures of DP z-scores and cardiometabolic risk factors. Cox proportional hazards models assessed relationships between DP scores and CVD incidence. Results An energy-dense, high-saturated-fat, and low-fiber DP was derived. A one-unit increase in the DP z-score between follow-ups was associated with an increase in weight [β (SE)] (1.71 ± 0.10 kg), waist circumference (1.49 ± 0.07 cm), BMI (0.60 ± 0.34 kg/m2), serum cholesterol (0.06 ± 0.01 mmol/l), and serum insulin (1.22 ± 0.17 mmol/l; all P < 0.0001), as well as in serum triglycerides (0.05 ± 0.02 mmol/l; P < 0.05), systolic blood pressure (1.05 ± 0.27 mmHg; P < 0.001), and diastolic blood pressure (0.55 ± 0.16 mmHg; P < 0.05). No significant association was observed between repeated measures of the DP z-scores and CVD incidence (HR = 0.96; 95% CI = 0.83-1.12). Conclusions An energy-dense, high-saturated-fat, and low-fiber DP was longitudinally associated with increases in cardiometabolic risk factors in severe obesity but not with CVD incidence.

Bariatric surgery is a life-changing treatment for patients with severe obesity, but little is known about its association with interpersonal relationships.To investigate if relationship status is altered after bariatric surgery.Changes in relationship status after bariatric surgery were examined in 2 cohorts: (1) the prospective Swedish Obese Subjects (SOS) study, which recruited patients undergoing bariatric surgery from September 1, 1987, to January 31, 2001, and compared their care with usual nonsurgical care in matched obese control participants; and (2) participants from the Scandinavian Obesity Surgery Registry (SOReg), a prospective, electronically captured register that recruited patients from January 2007 through December 2012 and selected comparator participants from the general population matched on age, sex, and place of residence. Data was collected in surgical departments and primary health care centers in Sweden. The current analysis includes data collected up until July 2015 (SOS) and December 2012 (SOReg). Data analysis was completed from June 2016 to December 2017.In the SOS study, information on relationship status was obtained from questionnaires. In the SOReg and general population cohort, information on marriage and divorce was obtained from the Swedish Total Population Registry.The SOS study included 1958 patients who had bariatric surgery (of whom 1389 [70.9%] were female) and 1912 matched obese controls (of whom 1354 [70.8%] were female) and had a median (range) follow-up of 10 (0.5-20) years. The SOReg cohort included 29 234 patients who had gastric bypass surgery (of whom 22 131 [75.6%] were female) and 283 748 comparators from the general population (of whom 214 342 [75.5%] were female), and had a median (range) follow-up of 2.9 (0.003-7.0) years. In the SOS study, the surgical patients received gastric banding (n = 368; 18.8%), vertical banded gastroplasty (n = 1331; 68.0%), or gastric bypass (n = 259; 13.2%); controls received usual obesity care. In SOReg, all 29 234 surgical participants received gastric bypass surgery. In the SOS study, bariatric surgery was associated with increased incidence of divorce/separation compared with controls for those in a relationship (adjusted hazard ratio [aHR] = 1.28; 95% CI, 1.03-1.60; P = .03) and increased incidence of marriage or new relationship (aHR = 2.03; 95% CI, 1.52-2.71; P < .001) in those who were unmarried or single at baseline. In the SOReg and general population cohort, gastric bypass was associated with increased incidence of divorce compared with married control participants (aHR = 1.41; 95% CI, 1.33-1.49; P < .001) and increased incidence of marriage in those who were unmarried at baseline (aHR = 1.35; 95% CI, 1.28-1.42; P < .001). Within the surgery groups, changes in relationship status were more common in those with larger weight loss.In addition to its association with obesity comorbidities, bariatric surgery-induced weight loss is also associated with changes in relationship status.

The aim of this study was to assess the effect of bariatric surgery (vertical gastroplasty, gastric banding, or gastric bypass) compared with usual care on the incidence of psoriasis and psoriatic arthritis (PsA) in the Swedish Obese Subjects study.This report includes 1,991 subjects who underwent bariatric surgery and 2,018 controls with obesity from the SOS study; none of them had psoriasis or PsA at baseline. Information about psoriasis and PsA diagnosis was retrieved through the Swedish National Patient Register and questionnaires.During follow-up for up to 26 years, bariatric surgery was associated with a lower incidence of psoriasis compared with usual care (number of events = 174; hazard ratio 0.65; 95% CI: 0.47-0.89; P = 0.008). Both smoking and a longer duration of obesity were independently associated with a higher risk for psoriasis. No significant difference was detected among the three surgical procedures in terms of lowering the risk of developing psoriasis. The association between bariatric surgery and psoriasis incidence was not influenced by baseline confounders. No significant difference in the risk of developing PsA (number of events = 46) was detected when comparing the surgery and the control groups.This study shows that bariatric surgery is associated with a lower risk of developing psoriasis compared with usual care.

Bariatric surgery in patients with obesity is generally considered to reduce cancer risk in patients with obesity. However, for colorectal cancer some studies report an increased risk with bariatric surgery, whereas others report a decreased risk. These conflicting results demonstrate the need of more long-term studies analyzing the effect of bariatric surgery on colorectal cancer risk. Therefore, data from the Swedish Obese Subjects (SOS) study, ClinicalTrials.gov identifier: NCT01479452, was used to examine the impact of bariatric surgery on long-term incidence of colorectal cancer. The SOS study includes 2007 patients who underwent bariatric surgery and 2040 contemporaneously matched controls who received conventional obesity treatment. Patients in the surgery group underwent gastric bypass (n = 266), banding (n = 376) or vertical banded gastroplasty (n = 1365). Information on colorectal cancer events was obtained from the Swedish National Cancer Registry. Median follow-up was 22.2 years (inter-quartile range 18.3–25.2). During follow up there were 58 colorectal cancer events in the surgery group and 67 colorectal cancer events in the matched control group with a hazard ratio (HR) of 0.79 (95% CI:0.55–1.12; p = 0.183). After adjusting for age, body mass index, alcohol intake, smoking status, and diabetes, the adjusted HR was 0.89 (95% CI:0.62–1.29; p = 0.551). When analyzing rectal cancer events separately- 19 events in the surgery group and 31 events in the control group-a decreased risk of rectal cancer with surgery was observed (HR = 0.56; 95% CI:0.32–0.99; p = 0.045, adjusted HR = 0.61 (95% CI:0.34–1.10; p = 0.099), while the risk of colon cancer was unchanged. To conclude- in this long-term, prospective study, bariatric surgery was not associated with altered colorectal cancer risk.

ObjectiveTo study the long-term effect of obesity and bariatric surgery on incidences of osteoarthritis and arthroplasty of hip and knee.DesignHazard ratios (HR) and incidence rates (IR) of osteoarthritis and arthroplasty of hip and knee were studied in the prospective, controlled, non-randomized Swedish Obese Subjects (SOS) study (bariatric surgery group, n = 2007; matched controls given usual obesity care, n = 2040) and the SOS reference cohort (n = 1135, general population). Osteoarthritis diagnosis and arthroplasty for osteoarthritis were captured from the National Swedish Patient Register. Median follow-up time was 21.2 (IQR 16.4–24.8), 22.9 (IQR 19.1–25.7), and 20.1 years (IQR 18.7–20.9) for the control group, surgery group and reference cohort, respectively.ResultsThe surgery group displayed lower incidence of hip osteoarthritis (IR 5.3, 95% CI 4.7–6.1) compared to controls (IR 6.6, 95% CI 5.9–7.5, adjHR 0.83, 95% CI 0.69–1.00) but similar incidence of hip arthroplasty. Similar incidence of knee osteoarthritis was observed in the surgery group and controls, but knee arthroplasty was more common in the surgery group (IR 7.4, 95% CI 6.6–8.2 and 5.6, 95% CI 4.9–6.4, adjHR 1.45, 95% CI 1.22–1.74). The reference cohort displayed lower incidences of osteoarthritis and arthroplasty of hip and knee compared with the surgery group and controls.ConclusionBariatric surgery did not normalize the increased risk of knee and hip osteoarthritis in patients with obesity but was associated with an increased incidence of knee arthroplasty compared to the control group. With the limitations inherent to the present data, additional studies are needed to confirm these results.Trial registrationclinicaltrials.gov Identifier: NCT01479452.

The aim of the present trial was to study the individual responsiveness to GH treatment in terms of body composition and to search for possible predictors of the response in GH-deficient adults. Sixty-eight patients (44 men and 24 women) with a mean age of 44.3 (1.2) yr and verified GH deficiency participated in a 2-phase treatment trial with an initial randomized, double blind, placebo-controlled, 6-month period, followed by an open treatment period, thereby ensuring all patients 12 months of GH treatment. Recombinant human GH was administered sc daily at bedtime, with a target dose of 12 micrograms/kg x day. GHBP was measured by ligand-mediated immunofunctional assay, and serum insulin-like growth factor I (IGF-I) was determined by RIA after acid-ethanol extraction, using a truncated IGF-I analog as the radioligand. Lean body mass (LBM) and body fat (BF) were determined by dual energy x-ray absorptiometry, and total body water (TBW) was determined by bioelectrical impedance. During the placebo control period, serum IGF-I,LBM, and TBW increased (P < 0.001), whereas BF decreased (P < 0.001) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo. After 12 months of GH treatment, the individual changes in BF ranged from -12.5 to 4.3 kg and from -4.5 to 10.1 kg in LBM. Age (P < 0.05) and baseline GHBP level (P < 0.01) were inversely correlated with the increase in LBM. The GH-induced increment in IGF-I and TBW was greater in men than in women (P < 0.01), whereas the decreases in BF were similar in men and women. This trial demonstrates the variability in responsiveness to GH administration in GH-deficient adults. The best response to GH was obtained in younger patients with low GHBP levels. Furthermore, men responded better than women.

Leptin seems to be involved in the regulation of energy balance, although little is known about the epidemiology of leptin with respect to prediction of weight gain and incidence of obesity-related diseases. The dual aim of this study is to document characteristics of leptin after long-term storage, and to describe its relation to body weight, from birth to old age, in an ongoing prospective study.A population-based sample of Swedish women was first examined at the ages of 38 to 60 and re-examined 24 years later. This study used 1358 frozen serum samples that had been stored 29 years for analysis of leptin concentrations and their relation to body weight history.Leptin values obtained from stored samples showed the same correlation with relative weight as that seen in a contemporary sample with similar demographic characteristics. Lower self-reported birth weight was associated with higher leptin levels in adulthood (p = 0.01), controlling for age and adult BMI. Prospective analyses revealed that high leptin in 38 to 46-year-olds predicted subsequent long-term weight gain (p = 0.003), although no significant associations were seen in women initially aged 50 or older.It is feasible to use frozen serum for studying leptin in relation to obesity and related developments many years later. High leptin level was a risk factor for subsequent weight gain in 38- and 46-year-old women. Retrospective analyses involving birth weight suggest that leptin resistance in adulthood might have fetal origins.

Abstract Objective: We have investigated the expression of several fibroblast growth factors (FGFs) and FGF‐receptors (FGFRs) in human adipose tissue and adipose‐tissue cell fractions obtained from both subcutaneous (sc) and omental (om) depots. Research Methods and Procedures: Adipose tissue (sc and om) was obtained from obese men. Gene expression was analyzed by DNA microarrays in triplicate ( n = 6) or by real‐time polymerase chain reaction ( n = 9). Results: FGF‐1, FGF‐2, FGF‐7, FGF‐9, FGF‐10, and FGF‐18 transcripts were detected in human adipose tissue. The expression of FGF‐2, FGF‐7, and FGF‐10 was similar in sc and om adipose tissue, whereas FGF‐1 and FGF‐9 were expressed at higher levels in the om adipose tissue. Expression of FGF‐18 was only detected in om adipose tissue in two of the subjects. Analysis of cell fractions revealed that FGF‐2 was only expressed in adipocytes; FGF‐7, FGF‐9, and FGF‐18 were expressed in the stroma‐vascular fraction; and FGF‐1 and FGF‐10 were expressed in both adipocytes and in the stroma‐vascular fraction. FGFR‐1 was expressed in both depots in all subjects and in both cell fractions, whereas FGFR‐2 expression was undetectable in whole adipose tissue but detectable in the adipocyte fractions from both sc and om depots. Discussion: We show that several members of the FGF family are expressed in human adipose tissue, and that the expression for some of the FGFs differs between sc and om adipose tissue. Taken together with previously published reports on the biological effects of FGFs on adipose cells, our results suggest that locally expressed FGFs could play role in the regulation of regional adipose tissue mass.

Context: We have previously identified nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1), an enzyme involved in the protection against oxidative stress, as a gene predominantly expressed in human adipocytes. Studies in mice deficient in NQO1 activity suggest that NQO1 may also play an important role in metabolism. Objective: The aim of this study was to explore the expression and regulation of NQO1 in human adipose tissue (AT) and isolated adipocytes. Patients and Results: The high expression of NQO1 in adipocytes was verified in human adipocytes and AT by real-time PCR. DNA microarray analysis showed that NQO1 was expressed at higher levels in large compared with small adipocytes, isolated from the same fat biopsy. Furthermore, NQO1 mRNA levels were positively correlated with adipocyte size (n = 7; P < 0.002). During an 18-wk diet regime (n = 24; mean weight loss 27 kg), the NQO1 expression in human sc AT was down-regulated (P < 0.0001), and mRNA levels correlated with body mass index (P = 0.0005), sc, and total abdominal AT areas, as determined by computerized tomography (P < 0.0001, both) and metabolic parameters. NQO1 mRNA levels were also positively correlated with aspartate aminotransferase (P = 0.0028) and alanine aminotransferase (P = 0.0219), markers known to be associated with severity of hepatic steatosis. Conclusions: NQO1 is highly expressed in human AT, particularly in large adipocytes. AT NQO1 expression is reduced during diet-induced weight loss, and the expression levels positively correlate with adiposity, glucose tolerance, and markers of liver dysfunction. Together, these findings indicate a role for NQO1 in the metabolic complications of human obesity.

Carboxylesterase 1 (CES1) has recently been suggested to play a role in lipolysis. Our aim was to study the regulation of CES1 expression in human adipose tissue. In the SOS Sib Pair Study, CES1 expression was higher in obese compared with lean sisters (n=78 pairs, P=8.7x10(-18)) and brothers (n=12 pairs, P=0.048). CES1 expression was higher in subcutaneous compared with omental adipose tissue in lean (P=0.027) and obese subjects (P=0.00036), and reduced during diet-induced weight loss (n=24, weeks 8, 16, and 18 compared to baseline, P<0.0001 for all time points). CES1 expression was higher in isolated adipocytes compared with intact adipose tissue (P=0.0018) and higher in large compared with small adipocytes (P=4.1x10(-6)). Basal and stimulated lipolysis was not different in individuals with high, intermediate, and low expression of CES1. Thus, CES1 expression was linked to body fat and adipocyte fat content but not to lipolytic activity.

To use a unique obesity-discordant sib-pair study design to combine differential expression analysis, expression quantitative trait loci (eQTLs) mapping and a coexpression regulatory network approach in subcutaneous human adipose tissue to identify genes relevant to the obese state.Genome-wide transcript expression in subcutaneous human adipose tissue was measured using Affymetrix U133 Plus 2.0 microarrays (Affymetrix, Santa Clara, CA, USA), and genome-wide genotyping data was obtained using an Applied Biosystems (Applied Biosystems; Life Technologies, Carlsbad, CA, USA) SNPlex linkage panel.A total of 154 Swedish families ascertained through an obese proband (body mass index (BMI) >30 kg m(-2)) with a discordant sibling (BMI>10 kg m(-2) less than proband).Approximately one-third of the transcripts were differentially expressed between lean and obese siblings. The cellular adhesion molecules (CAMs) KEGG grouping contained the largest number of differentially expressed genes under cis-acting genetic control. By using a novel approach to contrast CAMs coexpression networks between lean and obese siblings, a subset of differentially regulated genes was identified, with the previously GWAS obesity-associated neuronal growth regulator 1 (NEGR1) as a central hub. Independent analysis using mouse data demonstrated that this finding of NEGR1 is conserved across species.Our data suggest that in addition to its reported role in the brain, NEGR1 is also expressed in subcutaneous adipose tissue and acts as a central 'hub' in an obesity-related transcript network.

Adiponectin has been implicated in the pathogenesis of type 2 diabetes, but its role for incident diabetes, myocardial infarction, or stroke in obesity is unclear. The aim of this study was to analyze the associations between systemic levels of adiponectin and the aforementioned outcomes in a population with severe obesity at high risk of diabetes and cardiovascular events.We measured serum concentrations of total adiponectin in 3,299 participants of the prospective controlled Swedish Obese Subjects (SOS) Study (bariatric surgery group, n = 1,570; control group given usual care, n = 1,729). Median follow-up periods ranged between 10 and 13 years for different outcomes.In models containing both baseline adiponectin and 2-year changes in adiponectin, high baseline adiponectin and 2-year increases in adiponectin were associated with decreased risk of diabetes and myocardial infarction among controls. In the surgery group, the 2-year weight loss was paralleled by substantial increase in circulating adiponectin (1,807-1,958 ng/mL per 10-kg weight loss). However, neither baseline adiponectin nor 2-year increases in adiponectin were associated with risk of diabetes or myocardial infarction in the fully adjusted models in the surgery group. No associations were found for stroke in either group.Taken together, baseline adiponectin and 2-year changes were associated with incident diabetes and myocardial infarction in the control group but not in the surgery group. Baseline adiponectin did not predict treatment benefit of bariatric surgery.

Background Nutritional deficiencies, such as iron and vitamin B12 deficiencies, are potential adverse consequences of bariatric surgery. Long-term data on anaemia after bariatric surgery are largely lacking. We aimed to investigate the risk of anaemia, iron and vitamin B12 deficiency anaemia, and vitamin B12 deficiency over 20 years in individuals who had bariatric surgery or received usual obesity care. Methods The prospective, controlled Swedish Obese Subjects study recruited people with obesity via recruitment campaigns in the mass media and at primary health-care centres, and was done at 480 primary health-care centres and in 25 surgical departments in Sweden. Eligible participants were aged 37–60 years and had a BMI of either 34 kg/m2 or more (for men) or 38 kg/m2 or more (for women). Participants were excluded if they had undergone previous bariatric surgery or had contraindicating conditions. Two main groups were formed: those who chose bariatric surgery, the type of which was determined by the operating surgeon, and a contemporaneously matched control group, created by use of 18 matching variables, who received usual non-surgical obesity care that ranged from lifestyle advice to no treatment. Haemoglobin concentration was measured during examination visits at baseline and at 1 year, 2 years, 3 years, 4 years, 6 years, 8 years, 10 years, 15 years, and 20 years of follow-up. Anaemia was defined as a haemoglobin concentration of less than 120 g/L for women and 130 g/L for men. The primary, non-specified outcome was the incidence of anaemia, and was assessed in the as-treated population, which comprised only patients who received the actual treatment. The associations between treatment type and anaemia are expressed as unadjusted hazard ratios (HRs) and HRs adjusted for age, sex, BMI, menopausal status, education, diabetes, and hypertension, with 95% CIs. This study is registered in ClinicalTrials.gov, NCT01479452, and is closed to new participants, with follow-up ongoing. Findings Between Sept 1, 1987, and Jan 31, 2001, 6905 individuals were assessed for eligibility, of whom 5335 were eligible. Of these, we included 2007 patients who chose bariatric surgery (266 in the gastric bypass group, 1365 in the vertical-banded gastroplasty group, and 376 in the gastric banding group) and 2040 matched controls who received usual obesity care. During a maximum of 20 years and a median of 10 years (IQR 3–20) of follow-up, there were 133 anaemia events in the gastric bypass group, 359 in the vertical-banded gastroplasty group, 101 in the gastric banding group, and 261 in the control group. Compared with the control group (13 cases per 1000 person-years, 95% CI 11–14), the incidence of anaemia was higher in the gastric bypass group (64 cases per 1000 person-years, 53–74; HR 5·05, 95% CI 3·94–6·48; p<0·0001), the vertical-banded gastroplasty group (23 cases per 1000 person-years, 21–26; 2·67, 2·25–3·18; p<0·0001), and the gastric banding group (26 per 1000 person-years, 21–31; 2·76, 2·15–3·52; p<0·0001). These associations remained after adjustment. Interpretation Our findings highlight the increased risk of anaemia after bariatric surgery and the importance of long-term compliance to nutritional supplementation and monitoring to enable prevention and early detection of serious nutritional deficiencies after bariatric surgery. Funding Swedish Research Council, the Swedish state under the agreement between the Swedish Government and the county councils, the Swedish Diabetes Foundation, the Swedish Heart-Lung Foundation, and the Novo Nordisk Foundation.

Our knowledge of the role of the recently cloned ob-protein (leptin) in the regulation of body fat stores is largely derived from experiments performed in mice. Different mouse models exhibit abnormalities in ob-gene expression, with extreme overexpression in mice which lack bioactive ob-protein, have nonfunctional ob-receptors or hypothalamic lesions, and undetectable expression in mice with suggested defects in regulatory elements. The aim of this study is to examine if defects, corresponding to those in mice, exist in human obesity. Adipose tissue was obtained from 94 adult obese subjects and from six children who had developed obesity after surgery in the hypothalamic region. Total RNA was isolated and ob-gene expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot. The coding region of the ob-gene was sequenced in both directions in the 94 obese adults. No mutations were detected in the coding region of the ob-gene and ob-gene expression was detectable in all subjects and none of the subjects had an extreme overexpression. There was no systematic increase in ob-expression in obese children with hypothalamic disease compared to their healthy brothers and sisters. These results show that severe abnormalities involving the ob-gene, analogous to those described in mouse models, are rare in human obesity. We therefore conclude that the cloning and subsequent analysis of the ob-gene has not provided information that can, by itself, explain the genetic component in the development of human obesity.

We have demonstrated previously that pharmacological doses of oestradiol decreased leptin receptor expression in the hypothalamus. We therefore analysed leptin receptor expression during the oestrous cycle in the rat, to establish if acute changes in oestradiol affect leptin receptor expression under physiological conditions. Radioactive in situ hybridization histochemistry was used to measure the gene expression under investigation. Total leptin receptor transcript levels were lowest in pro-oestrus in the choroid plexus, these changes correspond inversely with levels of circulating oestradiol in the rat 4-day oestrous cycle. In contrast full-length leptin receptor levels in both arcuate and ventromedial nuclei did not correspond to the levels of total leptin receptor in the same areas of the hypothalamus or serum levels of oestradiol. Full-length leptin receptor expression in the arcuate nucleus was negatively correlated with neuropeptide Y (NPY) expression (r = 0.447, p < 0. 05) in the same nucleus. Arcuate nucleus NPY expression did not correlate significantly with the expression of total leptin receptors in the arcuate nucleus (r = 0.080) or serum leptin levels (r = 0.251). Our results demonstrate that leptin receptor expression is regulated during the oestrous cycle. The unchanged serum leptin levels during the oestrous cycle together with the correlation between the expression of leptin-RL and NPY provide circumstantial evidence that regulation of leptin receptor abundance in the hypothalamus governs the biological actions of leptin.

Journal Article Quantitative sequence-activity models (QSAM)—tools for sequence design Get access Jögen Jonsson, Jögen Jonsson Search for other works by this author on: Oxford Academic PubMed Google Scholar Torbjörn Norberg, Torbjörn Norberg 1Department of Microbiology, University of UmeäS-901 87, Umeä, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Lena Carlsson, Lena Carlsson 1Department of Microbiology, University of UmeäS-901 87, Umeä, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Claes Gustafsson, Claes Gustafsson 1Department of Microbiology, University of UmeäS-901 87, Umeä, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Svante Wold Svante Wold Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 21, Issue 3, 11 February 1993, Pages 733–739, https://doi.org/10.1093/nar/21.3.733 Published: 11 February 1993 Article history Received: 18 May 1992 Revision received: 29 December 1992 Accepted: 29 December 1992 Published: 11 February 1993

Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes.We sought to identify GC-regulated anti-inflammatory genes in nasal polyps.Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects.Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps.Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.

Growth hormone inhibits its own secretion in animals and man but the mechanism for this inhibition is unclear: both stimulation of somatostatin release and inhibition of GH-releasing factor (GRF) release have been implicated. We have now studied the GRF responsiveness of conscious male and female rats under conditions of GH feedback induced by constant infusion of exogenous human GH (hGH). Intravenous infusions of hGH (60 micrograms/h) were maintained for 3 to 6 h whilst serial injections of GRF(1-29)NH2 (0.2-1 microgram) were given at 45-min intervals. The GH responses were studied by assaying blood samples withdrawn at frequent intervals using an automatic blood sampling system. We have confirmed that male and female rats differ in their ability to respond to a series of GRF injections; female rats produced consistent GH responses for up to 13 consecutive GRF injections, whereas male rats showed a 3-hourly pattern of intermittent responsiveness. In female rats, multiple injections of GRF continued to elicit uniform GH responses during hGH infusions, whereas hGH infusions in male rats disturbed their intermittent pattern of responsiveness to GRF, and their regular 3-hourly cycle of refractoriness was prolonged. We suggest that this sex difference in GH feedback may be due to GH altering the pattern of endogenous somatostatin release differentially in male and female rats. Such a mechanism of GH autofeedback could be involved in the physiological control of the sexually differentiated pattern of GH secretion in the rat.

Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in which T-lymphocyte abnormalities have pathogenetic importance. In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax. This together with our previous findings of increased gene expression of Fas, interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes. We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.

Members of the cell death-inducing DFF45-like effector (CIDE) gene family have been shown to regulate lipid metabolism. In this article, we report that the third member of the human CIDE family, CIDEC, is down-regulated in response to a reduced caloric intake. The down-regulation was demonstrated by microarray and real-time polymerase chain reaction analysis of subcutaneous adipose tissue in 2 independent studies on obese patients undergoing treatment with a very low calorie diet. By analysis of CIDEC expression in 65 human tissues, we conclude that human CIDEC is predominantly expressed in subcutaneous adipocytes. Together, these observations led us to investigate the effect of decreased CIDEC expression in cultured 3T3-L1 adipocytes. Small interfering RNA-mediated knockdown of CIDEC resulted in an increased basal release of nonesterified fatty acids, decreased responsiveness to adrenergic stimulation of lipolysis, and increased oxidation of endogenous fatty acids. Thus, we suggest that CIDEC is a regulator of adipocyte lipid metabolism and may be important for the adipocyte to adapt to changes in energy availability.

Adipose tissue is an endocrine organ that produces and secretes adipokines. The aim of this study was to identify genes predominantly expressed in human subcutaneous adipocytes. For this purpose, an algorithm was developed and DNA microarray expression profiles from 33 human tissues and cell types were used to select genes. Inhibin beta B (INHBB; coding for the activin βB subunit) was identified and high expression in adipocytes was confirmed by real-time PCR and immunohistochemistry. INHBB expression in adipose tissue was down regulated by diet-induced weight loss (p < 0.001). Furthermore, INHBB expression was positively correlated to total (p < 0.001) and subcutaneous (p < 0.01) adipose tissue areas and serum levels of fasting insulin (p < 0.01) and cholesterol (p < 0.05). In conclusion, INHBB expression was high in human adipocytes, reduced by weight loss and adipose tissue INHBB mRNA levels correlated to metabolic risk factors. This suggests that activin B produced in adipocytes may play a role in the metabolic syndrome.

Lipid accumulation and inflammation are key hallmarks of the atherosclerotic plaque and macrophage uptake of oxidized low-density lipoprotein (oxLDL) is believed to drive these processes. Initial experiments show that supernatants from oxLDL treated macrophages could induce IL-1β production in naïve macrophages. To search for potential paracrine mediators that could mediate this effect a DNA microarray scan of oxLDL treated human macrophages was performed. This analysis revealed that oxLDL induced activation of heat shock protein (HSP) expression. HSPs have been implicated in the development of atherosclerosis, but the exact mechanisms for this is unclear. Extracellular heat shock protein 70 (HSP70) has been shown to elicit a pro-inflammatory cytokine response in monocytes and could therefore be a potential paracrine pro-inflammatory mediator. After 24 h of oxLDL treatment there was a significant increase of HSP70 concentrations in supernatants from oxLDL treated macrophages (oxLDLsup) compared to untreated controls (P < 0.05). OxLDLsup could induce both interleukin (IL)-1β and IL-12 secretion in naïve macrophages. We also demonstrate that the effect of oxLDLsup on cytokine production and release could be blocked by inhibition of HSP70 transcription or secretion or by the use of HSP70 neutralizing antibodies. This suggests that extracellular HSP70 can mediate pro-inflammatory changes in macrophages in response to oxLDL.

Context: Tenomodulin (TNMD), a putative angiogenesis inhibitor, is expressed in hypovascular connective tissues. Global gene expression scans show that the TNMD gene also is expressed in human adipose tissue and that its expression is regulated in response to weight reduction; however, more detailed information is lacking.

Using gene expression profiling, we aimed to identify genes that are predominantly expressed in human carotid atherosclerotic plaques. Such genes may be important in atherogenesis and pathophysiology of the plaque, and genes that encode for secreted proteins may be potential biomarkers for atherosclerosis and cardiovascular disease.DNA microarray generated expression profiles of human carotid atherosclerotic plaques were compared to expression profiles of 80 different human tissues and cell types, to identify plaque-specific genes.We identified the chemokine (C-C motif) ligand 18 (CCL18) as predominantly expressed in human carotid plaque. Immunohistochemistry showed that CCL18 protein was localized to a subset of macrophages in carotid plaques. Monocyte-derived macrophages from subjects with atherosclerosis had threefold higher expression of CCL18 than macrophages from control subjects (p=0.012). Subjects with A/G genotype of the rs2015086 SNP in the promoter region of the CCL18 gene had threefold higher macrophage expression of CCL18 than subjects with A/A genotype (p=0.049), but we found no association of this SNP with an increased risk of coronary heart disease. We also compared serum levels of CCL18 from subjects with symptomatic carotid artery disease with control subjects. There were no differences in serum levels of CCL18 between the two groups, however CCL18 correlated with measurements of adiposity.CCL18 is predominantly expressed in human atherosclerotic plaques and may participate in the atherosclerotic plaque formation.

Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 × 10(-8) and P= 3.1 × 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 × 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

The aim of this study was to determine the effect of bariatric surgery on the incidence of RA in participants of the Swedish Obese Subjects (SOS) study.The SOS is a longitudinal study aiming to assess the effect of bariatric surgery on mortality and obesity-related diseases. This report includes 2002 subjects with obesity who underwent bariatric surgery and 2034 matched controls; none of them had RA at baseline. Cases of incident RA were identified through the Swedish National Patient Register by searching for International Classification of Diseases codes. Both intention-to-treat analyses and per-protocol analyses are reported. In the per-protocol analysis, participants from the control group who underwent bariatric surgery later on during follow-up were censored at the time of surgery.During follow-up, 92 study participants developed RA. The median follow-up was 21 years (range 0-29). Bariatric surgery was neither associated with the incidence of RA in the intention-to-treat analysis [hazard ratio (HR) 0.92 (95% CI 0.59, 1.46), P = 0.74], nor in the per-protocol analysis [HR 0.86 (95% CI 0.54, 1.38), P = 0.53]. Weight change at the 2 year follow-up, expressed as the change in BMI compared with baseline, did not associate with the development of RA. Higher serum CRP levels and smoking associated with the future development of RA independent of other factors.We did not detect any association between bariatric surgery and the incidence of RA in subjects affected by obesity followed up for up to 29 years.(http://clinicaltrials.gov): NCT01479452.

BackgroundGallstone disease is a known short-term complication of bariatric surgery; little is known of the long-term incidence.ObjectivesThe aim of this study was to investigate the association between bariatric surgery and long-term incidence of gallstone disease.SettingsA total of 25 surgery departments and 480 primary healthcare centers in Sweden.MethodsThe Swedish Obese Subjects study is a prospective, controlled study comparing the effects of bariatric surgery with usual care with a follow-up of 20 years, including 4047 individuals. The current report includes all participants without previous or concomitant cholecystectomy (n = 3597). Operative techniques used in the surgery group (n = 1755) were gastric bypass (n = 236), vertical banded gastroplasty (n = 1202), and gastric banding (n = 317). The control group (n = 1842) received customary treatment for obesity. Gallstone disease was a predefined secondary endpoint in the Swedish Obese Subjects study and the primary endpoint of this report. Data were obtained by cross-checking our study database with the Swedish National Patient Register of diagnosis and procedures.ResultsIn the surgery and control groups, respectively, there were 307 and 252 first-time events of symptomatic gallstone disease and 230 and 170 cholecystectomies (log-rank P < .001, both outcomes). Bariatric surgery was associated with an increased risk of symptomatic gallstone disease, with a more pronounced risk during the first years of follow-up (P = .002) and an increased risk for cholecystectomy but with no time-varying effect (P = .213).ConclusionsBariatric surgery increases the risk for symptomatic gallstone disease and cholecystectomy, especially during the first years following treatment.

Accumulation of lipids and cholesterol by macrophages and subsequent transformation into foam cells are key features in development of atherosclerosis. Serum copper concentrations have been shown to be associated with cardiovascular disease. However, the mechanism behind the proatherogenic effect of copper is not clear. We used DNA microarrays to define the changes in gene expression profile in response to copper exposure of human macrophages. Expression monitoring by DNA microarray revealed 91 genes that were regulated. Copper increased the expression of seven cholesterogenic genes (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, IPP isomerase, squalene synthase, squalene epoxidase, methyl sterol oxidase, H105e3 mRNA and sterol-C5-desaturase) and low-density lipoprotein receptor (LDL-R), and decreased the expression of CD36 and lipid binding proteins. The expression of LDL-R and HMG CoA reductase was also investigated using real time PCR. The expression of both of these genes was increased after copper treatment of macrophages (P<0.01 and P<0.01, respectively). We conclude that copper activates cholesterogenic genes in macrophages, which may provide a mechanism for the association between copper and atherosclerosis. The effect of copper on cholesterogenic genes may also have implications for liver steatosis in early stages of Wilson's disease.

ABSTRACT There are GH-binding proteins (GHBPs) present in the blood of many species, and these correspond to the extracellular GH-binding domain of the GH receptor. In the rat, GHBP arises by alternative splicing of the GH receptor mRNA, but little is known of the physiological role of circulating GHBP, or its relationship with episodic GH secretion. We have developed a sensitive radioimmunoassay based on recombinant GHBP, and have measured rat GHBP levels in small samples of plasma from normal and GH-deficient dwarf rats. In normal adult rats, GHBP levels were two- to threefold higher in females than in males (16·6 ± 0·8 vs 6·4 ± 0·4μg/l, P &lt; 0·001), but this sex difference was not seen in dwarf rats. A continuous infusion of human GH in dwarf males raised plasma GHBP to 23·5 ± 3·5 μg/l compared with 6·7 ± 0·5 μg/l in sham-infused animals, whereas suppression of GH by continuous infusion of a long-acting somatostatin analogue in female dwarf rats had no effect on GHBP. In anaesthetized rats, large changes in plasma GH caused by i.v. administration of rat GH, somatostatin or GH-releasing factor did not affect GHBP acutely. Both GH and GHBP were also measured in serial blood samples from conscious normal and dwarf rats. A sexually dimorphic GH secretory pattern was observed in both strains. Males showed peaks and troughs of GH every 3 h varying over a 100-fold range, whereas females exhibited more continuous GH secretion. Despite the large fluctuations in endogenous GH, GHBP levels remained relatively constant in individual normal or dwarf males, as well as in females of both strains, and there was no significant correlation between GH and GHBP either in individual rats or as a group. Our results suggest that GHBP is GH-dependent in the longer term, and that the higher GHBP levels in female rats require their continuous GH secretory pattern. However, plasma GHBP levels remain stable and are not affected by acute changes in endogenous or exogenous GH. Journal of Endocrinology (1992) 135, 447–457

Functional recovery after experimental stroke in rats is enhanced by environmental enrichment by stimulating plastic changes in brain regions outside the lesion, but the molecular mechanisms are not known. We investigated the effect of environmental enrichment after focal cerebral ischemia on cognitive recovery and hippocampal gene expression using microarray analysis. Rats placed in enriched environment (EE) for 1 month after middle cerebral artery occlusion (MCAo) showed significantly improved spatial memory in the Morris water maze compared to rats housed alone after MCAo. Microarray analysis suggested several EE-induced differences in neuronal plasticity-related genes, but these changes could not be confirmed by quantitative real-time PCR. This study highlights some of the potential problems associated with gene expression profiling of brain tissues. Further studies at earlier time points and in additional subregions of the brain are of interest in the search for molecular mechanisms behind EE-induced neuronal plasticity after ischemic stroke.

We investigated the global gene expression response of endothelium exposed to shear stress and intraluminal pressure and tested the hypothesis that the two biomechanical forces induce a differential gene expression response pattern. Intact living human conduit vessels (umbilical veins) were exposed to normal or high intraluminal pressure, or to low or high shear stress in combination with a physiological level of the other force in a unique vascular ex vivo perfusion system. Gene expression profiling was performed by the Affymetrix microarray technology on endothelial cells isolated from stimulated vessels. Biomechanical forces were found to regulate a very large number of genes in the vascular endothelium. In this study, 1,825 genes were responsive to mechanical forces, which corresponds to 17% of the expressed genes. Among pressure-responsive genes, 647 genes were upregulated and 519 genes were downregulated, and of shear stress-responsive genes, 133 genes were upregulated and 771 downregulated. The fraction of genes that responded to both pressure and shear stimulation was surprisingly low, only 13% of the regulated genes. Our results indicate that the two different stimuli induce distinct gene expression response patterns, which can also be observed when studying functional groups. Considering the low number of overlapping genes, we suggest that the endothelial cells can distinguish between shear stress and pressure stimulation.

It has recently been shown that GH increases the number of available hepatic receptors for epidermal growth factor (EGF). In the present study the effects of the sexually dimorphic plasma GH pattern (higher pulsatility in male rats) on hepatic EGF binding and EGF receptor mRNA concentration were investigated. The specific binding of [125I]EGF to purified liver membranes was about 2-fold higher in male rats than in females on days 35, 50, and 80 of life. EGF receptor mRNA levels, as determined by an RNase protection solution hybridization assay, were higher in males only on days 47–50. Hypophysectomy on day 50 reduced the EGF receptor mRNA concentration to a level that did not differ between male and female rats. In hypophysectomized rats of both sexes, intermittent GH treatment (sc injections every 12 h for 7 days) enhanced hepatic EGF receptor mRNA concentrations to normal male levels, while continuous GH administration was less effective. Northern blot analysis indicated that transcripts with apparent sizes of 9.5 and 6.6 kilobases were dependent on the plasma GH pattern. Intermittent iv GH replacement therapy for 5 days given at 3-h intervals by an automatic iv infusion system increased the hepatic EGF receptor mRNA concentration as well as specific EGF binding, whereas continuous iv GH infusion was ineffective. These results show that a pulsatile plasma GH pattern, similar to that of male rodents, is markedly more effective in enhancing hepatic EGF receptor mRNA levels and EGF binding than a continuous feminine GH pattern. These results are consistent with a pretranslatory stimulation of EGF receptor synthesis by pulsatile GH.

Aims . Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods . Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery () or conventional treatment (). Mean follow-up is 10.8 years. Results . Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion . Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD.

The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study.Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance.In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2-4.2% (P < 10(-14)) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R(2) = 0.4-1.1%; 3.8 × 10(-6) < P < 3 × 10(-3)), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10(-4) < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C.SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

Abstract Background We have shown that high mid‐life central adiposity may increase the risk for dementia after 32 years. Leptin, an adipose tissue hormone, is correlated with adiposity measures and may contribute to a better etiological understanding of the relationship between high adiposity and dementia. We explored the relationship between serum leptin in mid‐life and dementia, which is a late‐life outcome. Methods A longitudinal cohort study, the Prospective Population Study of Women, in Gothenburg, Sweden, includes a representative sample of 1462 women followed from mid‐life ages of 38 to 60 years to late‐life ages of 70 to 92 years. Women were examined in 1968, 1974, 1980, 1992, and 2000 using neuropsychiatric, anthropometric, clinical, and other measurements. Serum leptin was measured on samples collected at the 1968 baseline examination, after storage at −20°C for 29 years. Cox proportional hazards regression models estimated incident dementia risk by baseline leptin. Logistic regression models related leptin levels to dementia among surviving participants 32 years later. All models were adjusted for multiple potential confounders. Results Mid‐life leptin was not related to dementia risk using Cox or logistic regression models. This was observed despite positive baseline correlations between leptin and adiposity measures, and given our previous report of high mid‐life waist‐to‐hip ratio being related to a twofold higher dementia risk. Conclusions Leptin is not a mid‐life marker of late‐life dementia risk in this population sample of Swedish women born between 1908 and 1930.

Adipocytes secrete many proteins that regulate metabolic functions. The gene inter‐α (globulin) inhibitor H5 ( ITIH‐5 ) encodes a secreted protein and is known to be expressed abundantly in the placenta. However, using gene expression profiles data we observed high expression of ITIH‐5 in adipose tissue. The aim of this study was to test the hypothesis that ITIH‐5 is strongly expressed in human adipocytes and adipose tissue, and is related to obesity and clinical metabolic variables. ITIH‐5 adipose tissue mRNA expression was analyzed with DNA microarray and real‐time PCR, and its association with clinical variables was examined. ITIH‐5 protein expression was analyzed using western blot. ITIH‐5 mRNA expression was abundant in human adipose tissue, adipocytes, and placenta, and higher in subcutaneous (sc) compared to omental adipose tissue ( P &lt; 0.0001). ITIH‐5 mRNA and protein expression in sc adipose tissue were higher in obese compared to lean subjects ( P &lt; 0.0001 and P &lt; 0.001, respectively). ITIH‐5 mRNA expression was reduced after diet‐induced weight loss ( P &lt; 0.0001). ITIH‐5 mRNA expression was associated with anthropometry and clinical metabolic variables. In conclusion, ITIH‐5 is highly expressed in sc adipose tissue, increased in obesity, down regulated after weight loss, and associated with measures of body size and metabolism. Together, this indicates that ITIH‐5 merits further investigation as a regulator of human metabolism.