Lars Sjöström

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.

Weight loss is associated with short-term amelioration and prevention of metabolic and cardiovascular risk, but whether these benefits persist over time is unknown.

It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients.In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/=30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat.Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001).Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT or NGT [correction].

A longitudinal population study of 1462 women aged 38-60 was carried out in Gothenburg, Sweden, in 1968-9. In univariate analysis the ratio of waist to hip circumference showed a significant positive association with the 12 year incidence of myocardial infarction, angina pectoris, stroke, and death. The association with incidence of myocardial infarction remained in multivariate analysis and was independent of age, body mass index, smoking habit, serum cholesterol concentration, serum triglyceride concentration, and systolic blood pressure. The relation between the ratio of waist to hip circumference and the end points of myocardial infarction, angina pectoris, stroke, and death was stronger than for any other anthropometric variable studied.

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.

Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.

We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2-year period.743 patients (body-mass index 28-47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet.From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10.2% [10.3 kg] vs 6.1% [6.1 kg]; LSM difference 3.9 kg [p<0.001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0.001). Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2, compared with a mean regain of 2.5 kg in patients who continued on placebo (p<0.001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments.Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.

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.

To evaluate the construct validity of the Three-Factor Eating Questionnaire (TFEQ) in obese men and women.A total of 4377 middle-aged, obese subjects in the Swedish Obese Subjects (SOS) study.The total sample was randomly split into two data subsets and psychometric testing was performed separately in each sample. Multitrait/multi-item analysis was conducted to test scaling assumptions and factor analysis was used to test the factor structure. Measures of mental well-being (MACL, HAD) were used for testing criterion-based validity.The Cognitive Restraint factor was consistently reproduced and scaling analysis demonstrated strong item-scale discriminant validity, while the item-scale convergent validity was unsatisfactory. The internal structure of the Disinhibition scale was weak. Most Disinhibition and Hunger items grouped in one global factor labeled Uncontrolled Eating. A third cluster containing items on Emotional Eating was also identified. The obtained three-factor structure was cross-validated and replicated across subgroups by gender, age and BMI.The original TFEQ factor structure was not replicated. A short, revised 18-item instrument was constructed, representing the derived factors of Cognitive Restraint, Uncontrolled Eating and Emotional Eating. The most efficient items were used to boost both the convergent and discriminant validity of the scales.

In a double blind, cross-over placebo-controlled trial, we studied the effects of 26 weeks of replacement therapy with recombinant human GH on body composition, metabolic parameters, and well-being in 10 patients with adult-onset GH deficiency (GHD). All patients received appropriate thyroid, adrenal, and gonadal replacement therapy. The dose of recombinant human GH was 0.25-0.5 U/kg.week (0.013-0.026 mg/kg.day) and was administered sc daily at bedtime. One patient was withdrawn from the study because of edema and atrial fibrillation. Body composition was estimated with three independent methods: computed tomography, bioelectric impedance, and total body potassium combined with total body water assessments. The Comprehensive Psychological Rating Scale and the Symptom Check List-90 were used to assess any change in psychopathology. After 26 weeks of treatment, adipose tissue (AT) mass decreased 4.7 kg (P < 0.001). Subcutaneous AT decreased by an average of 13%, whereas visceral AT was reduced by 30%. Muscle volume increased by 2.5 kg (5%; P < 0.05). According to the four-compartment model derived from assessments of total body potassium and total body water, body cell mass and extracellular fluid volume increased significantly by 1.6 and 3.0 kg, whereas body fat decreased by 6.1 kg. Results obtained by the bioelectric impedance technique were similar. The mean (+/- SD) concentrations of insulin-like growth factor-I increased from 0.26 (0.06) at baseline to 2.56 (1.55) and 2.09 (1.03) kU/L after 6 and 26 weeks of treatment. Calcium and serum phosphate, osteocalcin, and procollagen-III concentrations were significantly higher, and intact PTH concentrations were reduced after 6 and 26 weeks of treatment, respectively. Total and free T3 concentrations were significantly increased after 6 and 26 weeks of treatment, whereas free T4 concentrations were reduced at 6 weeks, but after 26 weeks, free T4 concentrations had returned to pretreatment values. Finally, after 26 weeks of treatment, there was a decrease in the Comprehensive Psychological Rating Scale score (P < 0.05). The results show that GH replacement in GHD adults results in marked alterations in body composition, fat distribution, and bone and mineral metabolism and reduces psychiatric symptoms. Finally, we conclude that the observed beneficial effects of replacement therapy with GH are of sufficient magnitude to consider treatment of GHD adults.

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.

Abstract SJÖSTRÖM, c. DAVID, LAUREN LISSNER, HANS WEDEL, and LARS SJÖSTRÖM. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res . Objective : To examine the effect of a large, long standing and intentional weight reduction on the incidence of diabetes, hypertension and lipid disturbances in severely obese individuals as compared to weight‐stable obese controls. Research Methods and Procedures : The ongoing prospective SOS (Swedish Obese Subjects) intervention consists of a surgically treated group and a matched control group obtaining conventional obesity treatment. This report is based on 845 surgically treated patients and 845 controls (BMI41. 0±4. 6 kg/m 2 (mean±standard deviation [S])) followed for 2 years. Results : Surgically treated patients lost 28±15 kg and controls 0. 5±8. 9 kg ( p &lt;0. 0001). Two‐year incidence of hypertension, diabetes, hyperinsulinemia, and lipid disturbances was compared in the two treatment groups. Adjusted odds ratios (95% CI) for the surgically treated group versus controls were 0. 38 (0. 22, 0. 65) for hypertension, 0. 02 (0. 00, 0. 16) for diabetes, 0. 10 (0. 03, 0. 28) for hyperinsulinemia, 0. 10 (0. 04, 0. 25) for hypertriglyceridemia, 0. 28 (0. 16, 0. 49) for low HDL‐cholesterol and 1. 24 (0. 84, 1. 8) for hypercholesterolemia. Compared to controls, the 2‐year recovery rates from hypertension, diabetes, hypo‐HDL, and hypertriglyceridemia were significantly higher in the surgically treated group. Discussion : Intentional weight loss in the obese causes a marked reduction in the 2‐year incidence of hypertension, diabetes and some lipid disturbances. The results suggest that severe obesity can and should be treated.

Twenty-three healthy men (age 25 to 50 years), covering a wide range of fatness and body fat distribution, were studied. An oral glucose tolerance test was performed and adipose tissue areas were calculated from computed tomography (CT) scans made at the level of L4/L5. Visceral fat area was associated with elevated concentrations of insulin and C-peptide and with glucose intolerance before and after the oral glucose load. Concentrations of sex-hormone-binding globulin (SHBG), as well as total and free testosterone, were negatively correlated with waist/hip circumference ratio and visceral fat area and also negatively associated with increased glucose, insulin, and C-peptide concentrations. In multiple linear regression, adjusting for age, body mass index, and visceral fat area, serum concentrations of free testosterone were still negatively correlated with glucose, insulin, and C-peptide levels. Without claiming any causality in the observed associations, we conclude that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.

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.

OBJECTIVE: To examine the effects of weight loss on health-related quality of life (HRQL) in subjects with severe obesity. DESIGN: Controlled clinical trial of the outcomes of surgical vs conventional weight reduction treatment. SUBJECTS: The first 487 surgical cases and their conventionally treated, matched controls were followed for two years in the Swedish Obese Subjects (SOS) intervention study. MEASUREMENTS: A battery of generic and study-specific self-assessment instruments or subscales was used to characterize HRQL in the severely obese (BMI) ≥34 kg/m2 for males and BMI ≥38 kg/m2 for females). Measures of general health perceptions (general health rating index; current health), mental well-being (mood adjective check list; pleasantness, activation and calmness), mood disorders (hospital anxiety and depression scale; anxiety and depression) and social interaction (sickness impact profile), were supplemented by obesity-specific modules on obesity-related psychosocial problems and eating behavior (three-factor eating questionnaire; restrained eating, disinhibition and perceived hunger). Assessments were conducted prior to treatment and repeated after 6, 12 and 24 months. RESULTS: Poor HRQL before intervention was dramatically improved after gastric restriction surgery, while only minor fluctuations in HRQL scores were observed in the conventionally treated controls. Peak values were observed in the surgical group at 6 or 12 months after intervention with a slight to moderate decrease at the two-year follow-up. The positive changes in HRQL after two years were related to the magnitude of weight loss, that is, the greater the weight reduction, the greater the HRQL improvements. Eating behavior improved accordingly. CONCLUSION: Quality of life in the severely obese is improved by substantial weight loss. Most patients benefit from weight reduction surgery, while HRQL in surgical patients with minor reduction in overweight is less positive. Further research is needed to determine outcome predictors of the surgical management of severe obesity and to ensure that HRQL improvements are maintained.

Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95).Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver.

To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors.This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured.Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p<0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment.Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.

To investigate the effects of obesity and weight loss on cardiovascular autonomic function, we examined 28 obese patients referred for weight-reducing gastroplasty, 24 obese patients who received dietary recommendations, and 28 lean subjects. Body weight, blood pressure, and 24-hour urinary norepinephrine excretion were measured, and time and frequency domain indexes of heart rate variability (HRV) were obtained from 24-hour Holter recordings. A measure of long-term HRV, the SD of all normal RR intervals (SDANN), was used as an index of sympathetic activity and the high-frequency (HF) component of the frequency domain, reflecting short-term HRV, as an estimate of vagal activity. All 3 study groups were investigated at baseline, and the 2 obese groups were reexamined at 1-year follow-up. Obese patients had higher blood pressure, higher urinary norepinephrine excretion, and attenuated SDANN and HF values than lean subjects (p <0.01). Obese patients treated with surgery had a mean weight loss of 32 kg (28%), whereas the obese group treated with dietary recommendations remained weight stable (p <0.001). At follow-up the weight-loss group displayed decreases in blood pressure and norepinephrine excretion and showed increments in SDANN and HF values. These changes were significantly greater than those observed in the obese control group (p <0.05). Our findings suggest that obese patients have increased sympathetic activity and a withdrawal of vagal activity and that these autonomic disturbances improve after weight loss.

Middle-aged men with abdominal obesity were treated in a double-blind study with moderate doses of transdermal preparations of testosterone (T), dihydrotestosterone (DHT), or placebo. This resulted in moderately elevated T concentrations and marked decreases in follicle stimulating and luteinizing hormones in the group treated with T, while the DHT group showed elevated DHT, markedly lower T values, and less diminution of gonadotropin concentrations. In the group treated with T visceral fat mass decreased (measured by computerized tomography) without significant changes in other depot fat regions. Lean body mass did not change. In the group treated with T, glucose disposal rate, measured with the euglycemic hyperinsulinemic clamp method, was markedly augmented. Plasma triglycerides, cholesterol, and fasting blood glucose concentrations as well as diastolic blood pressure decreased. There were no such changes in the DHT or placebo treatment groups. The men treated with T reported increased well-being and energy. In none of the groups did prostate volume, specific prostate antigen concentration, genito-urinary history, or urinary flow measurement change. It is suggested that supplementation of abdominal obese men with moderate doses of T might have several beneficial effects.

Mass, morphology, and metabolism of total adipose tissue and its subcutaneous, visceral, and retroperitoneal subcompartments were examined in 16 men with a wide variation of total body fat. Computerized tomography (CT) scans showed that the intraabdominal fat mass comprised approximately 20% of total fat mass. Visceral and retroperitoneal fat masses were approximately 80% and 20% of total intraabdominal fat mass, respectively. Enlargement of intraabdominal fat depots was due to a parallel adipocyte enlargement only. Direct significant correlations were found between these adipose tissue masses and blood glucose and plasma insulin levels, blood pressure, and liver function tests, while glucose disposal rate during euglycemic glucose clamp measurements at submaximal insulin concentrations (GDR), plasma testosterone, and sex hormone-binding globulin concentrations correlated negatively. The correlations for glucose, insulin, and GDR were strongest with visceral fat mass. Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues. Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines. Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin. Both lipid uptake and lipolytic sensitivity and responsiveness showed strong correlations (r = 0.8 to 0.9) to blood glucose and plasma insulin concentrations and also to the GDR (negative), while no such correlations were found with lipid uptake in subcutaneous or retroperitoneal abdominal adipose tissues. Taken together, these results suggest a higher turnover of lipids in visceral than in the other fat depots, which is closely correlated to systemic insulin resistance and glucose metabolism in men.

To investigate snacking frequency in relation to energy intake and food choices, taking physical activity into account, in obese vs reference men and women.Cross-sectional, descriptive study.In total, 4259 obese, middle-aged subjects (1891 men and 2368 women) from the baseline examination of the XENDOS study and 1092 subjects (505 men and 587 women) from the SOS reference study were included.A meal pattern questionnaire describing habitual intake occasions (main meals, light meals/breakfast, snacks, drink-only), a dietary questionnaire describing habitual energy and macronutrient intake and a questionnaire assessing physical activity at work and during leisure time were used.The obese group consumed snacks more frequently compared to the reference group (P<0.001) and women more frequently than men (P<0.001). Energy intake increased with increasing snacking frequency, irrespective of physical activity. Statistically significant differences in trends were found for cakes/cookies, candies/chocolate and desserts for the relation between energy intake and snacking frequency, where energy intake increased more by snacking frequency in obese subjects than in reference subjects.Obese subjects were more frequent snackers than reference subjects and women were more frequent snackers than men. Snacks were positively related to energy intake, irrespective of physical activity. Sweet, fatty food groups were associated with snacking and contributed considerably to energy intake. Snacking needs to be considered in obesity treatment, prevention and general dietary recommendations.

Ten obese patients were subjected to physical training, which resulted in an increased maximal oxygen consumption and an increased isometric muscle strength. Body weight increased, due primarily to an increase in body fat, but also, in some cases, to an increase in body cell mass, determined by isotope dilution techniques. Fat cell diameter was unchanged. Peroral glucose tolerance test with plasma radioimmuochemically determined insulin in these patients showed no changes in blood glucose values after training but a marked decrease in insulin values. This was interpreted to be due to an increased insulin sensitivity of tissues. Since the body fat mass was not decreased it was not considered likely that the increased insulin sensitivity was due to adipose tissue factors. This augmentation of insulin sensitivity was furthermore not related to the increase in body cell mass and therefore probably not to an increase in muscle mass. It was concluded that muscle probably is an important determinant for insulin sensitivity in obesity.

Diameters of fat cells in adipose tissue slices, floating in an isoosmolar solution, were measured under a microscope.The slices were obtained from percutaneous biopsies by freeze-cutting after brief formaldehyde fixation.All cells in a given part of the slice were measured, thus avoiding selection.A normal distribution of fat cell diameters could be demonstrated with this method, as has been found with previously described methods.The error of the method was 2.6% for diameter and 8.0% for weight determinations.Storage of adipose tissue at 4OC for 48 hr had no effects on cell size determinations.Results with this micrcscopic method were compared with those obtained from a previously described method for automatic determinations of osmium-fixed fat cells.The latter method was slightly modified by using a viscous electrolyte, which prevented sedimentation of large fat cells, and by using sonication to complete cell separation.The methods agreed closely.A method for calculating mean fat cell weight using osmiumfixed fat cells is described, which makes determinations of sample wet weight and ratio of lipid to wet weight unnecessary.

T o identify cells developing into adipocytes by accumulation of triglyceride, rat epididymal fat pad cells from small rats were exposed to 3H-labeled chylomicron fatty acids in vivo and then liberated with collagenase.Tissue remnants were removed by filtration and mature fat cells by flotation.Aggregating cells were then removed by filtration through a 25-pm nylon screen.Further purification of cells labeled in vivo was obtained by removing floating cells from those adhering to the bottom of a culture dish.The adhering cells multiplied to a confluent monolayer when cultured in Medium 199 containing serum, glucose, insulin, and a triglyceride emulsion.The cells then gradually enlarged due to granulation of the cytoplasm by a lipid-staining material.After about 2 weeks these granules had coalesced forming mature adipocytes of typical signet-ring appearance.Free adipocytes could then be recovered from the cultures by collagenase treatment.After about 2 weeks of culture these cells had the same size (about 30 pm) as adipocytes recovered in the original collagenase preparation of the rat epididymal fat pad.They contained triglyceride lipase activity and incorporated glucose into triglycerides to the same extent as cells developed in vivo but had higher lipoprotein lipase activity.In vitro, heparin in a low concentration, prostaglandin E,, isobutylmethylxanthine, and cholera toxin markedly promoted the development of these cells into adipocytes.This could be shown to occur almost completely indicating that this fraction of cells was homogeneous and consisted of cells with the capacity to form adipocytes.The duplication time was about 2

Body fat and adipose tissue fat cell size and number were determined in a group of obese patients and in controls. These variables were analyzed at different degrees of obesity and compared with metabolic variables, including blood glucose and plasma insulin during glucose tolerance testing and blood lipids. Fat cell size was responsible for the increase of obese adipose tissue at a moderate degree of obesity. With more severe obesity, fat cell number becomes increasingly important and dominates as a factor contributing to obesity. Under conditions of unrestricted diet and activity, plasma insulin correlated positively with fat cell size but not with body fat, and tended to show a negative correlation with fat cell number. The factor in adipose tissue associated with plasma insulin increase is thus probably the fat cell size. The results suggest two forms of obesity. One is characterized by a hypertrophy of fat cells and is of a moderate degree (hypertrophic obesity). This type of obesity is associated with metabolic disturbances. Increased fat cell size might not be a primary factor in this form of obesity, but rather another symptom of metabolic disturbance. The other form (hyperplastic obesity) has an increased number of fat cells and is associated with much more severe obesity, particularly since fat cell size is often increased also in these patients.

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.

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.

Abstract —The beneficial effects of weight loss in the obese have been widely accepted. Still, there is a lack of controlled studies displaying large maintained weight losses over long periods (&gt;4 years). We wanted to examine the results of long-standing intentional weight loss on the development of diabetes and hypertension in severely obese individuals over an 8-year period. In the ongoing prospective Swedish Obese Subjects (SOS) study, 346 patients awaiting gastric surgery were matched with 346 obese control subjects on 18 variables by a computerized matching program. The controls were drawn from a registry consisting of 1508 obese potential controls examined at primary health care centers in Sweden. Of the 692 selected patients (body mass index 41.2±4.7 kg/m 2 [mean±SD]), 483 (70%) were followed for 8 years. No significant weight changes occurred in the obese control group over 8 years. Gastric surgery resulted in a maximum weight loss of −31.1±13.6 kg after 1 year. After 8 years, the maintained weight loss was still 20.1±15.7 kg (16.3±12.3%). Whereas this weight reduction had a dramatic effect on the 8-year incidence of diabetes (odds ratio 0.16, 95% CI 0.07 to 0.36), it had no effect on the 8-year incidence of hypertension (odds ratio 1.01, 95% CI 0.61 to 1.67). A differentiated risk factor response was identified: a maintained weight reduction of 16% strongly counteracted the development of diabetes over 8 years but showed no long-term effect on the incidence of hypertension.

<h3>Background</h3> Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. <h3>Objective</h3> To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo. <h3>Methods</h3> We pooled data from 675 obese (body mass index, 30-43 kg/m²) adults at 39 US and European research centers in 3 randomized, double-blind, placebo-controlled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment. <h3>Main Outcome Measures</h3> The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels. <h3>Results</h3> The mean length of follow-up was 582 days. Subjects who were treated with orlistat lost more weight (mean±SEM, 6.72±0.41 kg from initial weight) than subjects who received placebo (3.79±0.38 kg;<i>P</i>&lt;.001). A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose levels normalized in more subjects after orlistat treatment (71.6%) vs placebo (49.1%;<i>P</i>=.04). <h3>Conclusions</h3> The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.

Twenty-seven women with varying degrees of obesity were physically trained for 6 mo on an ad lib. diet. Body fat changes were positively correlated with the number of fat cells in adipose tissue. Obese women with fewer fat cells decreased in weight during training whereas women with severe obesity and an increased number of fat cells even gained weight. Blood pressure decreased consistently after training. Blood pressure elevation was not associated with body fat mass, nor was a decrease in blood pressure associated with a decrease in body fat or with pretraining blood pressure level. There were, instead, correlations between decreases in blood pressure on the one hand and initial concentrations and decreases in plasma insulin and triglycerides and blood glucose on the other. These results suggest an association between elevated blood pressure and metabolic variables. The possibility of treating and preventing early essential hypertension with methods that also correct the metabolic derangement, such as diet and exercise, should be given high priority in further research.

The adipose tissue volumes of 12 women were determined by computed tomography (CT). Body weight ranged from 46 to 129 kg. Nine or twenty-two transsectional scans were examined with respect to the adipose tissue area. The total adipose tissue volume (ATCT22 or ATCT9) was calculated by assuming linear changes in the adipose tissue area between adjacent scans. Body fat (BF) was also calculated from total body potassium (BF40K), from total body water (BFTHO), and from both these determinations (BF40K + THO). Body mass index (BMI) was calculated by dividing body weight (BW) by height2 (H2). ATCT22, ATCT9, and BFK were more closely related to BW and BMI than were BFTHO and BF40K + THO. When ATCT was used as a standard, the optimal index of adiposity based on BW and H was in the range BW/H0.8 to BW/H1.2. From the CT and 40K measurements it was possible to deduce that the potassium content is 62 mmol/kg fat free mass and 73-75 mmol/kg lean body mass. The error of ATCT9 was 0.6%, while that of BF40K was at least three to four times larger. It is concluded that the CT-based AT determination is the most reproducible method so far available. The technique might turn out to be of great value in human energy balance experiments.

The prevalences of several risk factors and diseases are dramatically increased in obesity. In contrast, considerable inconsistencies have been reported for the relationship of obesity to the incidence of cardiovascular disease and total mortality. Suggested reasons for these inconsistencies have been confounders and surrogate risk factors, but the single most important cause is that far-reaching conclusions have been drawn from small short-term studies. Several large studies have recently proven that the incidence of cardiovascular disease is increased in obesity. Correct classification of obesity and its subgroups is also of great importance. Visceral obesity constitutes one subgroup at high risk. It seems possible to link diabetes, hypertriglyceridemia, reduced fibrinolysis, and hypertension to elevated portal free fatty acid concentrations because of an increased visceral adipose tissue depot. The quantitation of visceral adipose tissue has been improved by techniques based on computed tomography (CT) and by CT-calibrated anthropometric methods. Results from controlled intervention studies of obesity are entirely lacking but one such study has been started.

OBJECTIVE: The Obesity-related Problems scale (OP) is a self-assessment module developed to measure the impacts of obesity on psychosocial functioning. Our principal aim was to evaluate the construct validity and responsiveness of the OP scale. Our specific aims were to test: (1) the psychometric performance of OP; (2) if OP scores differed by gender and weight category; (3) if OP scores are inversely related to mental well-being; (4) if weight reduction in the obese is accompanied by improvements in psychosocial functioning (OP). SUBJECTS: Four samples were used: 6863 subjects in the SOS cross-sectional study; 2128 in the SOS intervention study; 1017 nonobese in the SOS reference study; and 3305 obese subjects in the XENDOS study. MEASUREMENTS: Psychosocial functioning was measured by OP. Overall mood was measured by MACL. Anxiety and depression symptoms were measured by HAD. RESULTS: Psychometric testing provided strong support for the construct validity of OP. Factor analysis confirmed the homogeneity of the construct and multitrait/multi-item scaling analysis demonstrated strong item-convergent/discriminant validity. Reliability coefficients were high and floor and ceiling effects were small. Psychometric results were cross-validated and replicated in subgroups by gender, age and body mass index (BMI). As expected, large differences in OP were observed between obese and nonobese (P<0.0001). Obese women reported more weight-related psychosocial problems than obese men (P<0.0001). Psychosocial disturbances (OP) among the obese were significantly related to poor mood (MACL; P<0.0001) and anxiety and depression symptoms (HAD; P<0.0001). Change in OP over time was strongly correlated with weight loss (P<0.0001). A distinct dose–response effect between weight reduction and improvements in OP was demonstrated. Scores on psychosocial functioning (OP) and mental well-being (MACL, HAD) in nonobese (BMI<30) surgical patients at 4-y follow-up were equal to scores observed in nonobese reference subjects (NS). CONCLUSION: OP is a psychometrically valid obesity-specific measure suitable for evaluating HRQL effects of obesity interventions. The negative impact of obesity on psychosocial functioning is considerable and disturbances are connected with poor mental well-being. Weight reduction in the obese is followed by improvements in both psychosocial functioning and mental well-being.

Recent information indicates that the capacity of man to store carbohydrate energy by transformation into fatty acids synthetized de novo is very limited in adipose tissue as well as in liver and intestine. This seems to be in contrast to other species such as the rat where de novo fatty acid synthesis can be induced to a high capacity of glucose removal. This leaves man with a limited capacity to store excess carbohydrate. The remaining possibilities are both the main glycogen stores in liver and in muscle. The latter is by far the largest. The capacity of muscle to assimilate glucose is dependent on its glycogen content that in turn is dependent on previous glycogen depletion to supply energy for muscle contraction. Man might, thus, be uniquely limited in the capacity to dispose of extra carbohydrate in the sedentary state. This might speculatively be thought to be an explanation for a carbohydrate excess syndrome in the sedentary state that may well increase the risk for obesity, hyperinsulinemia, and diabetes mellitus. The logical treatment for such a syndrome then is either a decreased intake of energy as carbohydrate or an increased disposal of carbohydrate energy by exercise. Exercise has, indeed, been shown to have such effects both after physical training programs and, perhaps more pertinent to the question, during a few days after a single exercise bout that has consumed a large amount of muscle glycogen.

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.

Objective: To characterize meal patterns in relation to obesity in Swedish women using a simple instrument describing meal frequency, meal types and temporal distribution. Design: Cross-sectional parallel group design. Subjects: Eighty-three obese women from the Swedish Obese Subjects (SOS) study were compared with 94 reference women, randomly recruited from the population. Method: A new, simplified and self-instructing questionnaire was used to assess meal patterns. Usual meal pattern was reported as time and meal type for each intake episode during a typical day. Results: The obese women consumed 6.1 meals/day compared with 5.2 meals/day among the reference women (P<0.0001). All types of meals except 'drink meals' were significantly more frequently consumed in the obese group. The obese women also displayed a different meal pattern across the day, consuming a larger number of meals later in the day. As a result a larger fraction of each obese woman's total meals were consumed in the afternoon and in the evening/night. There was no difference in the number of obese vs reference women consuming breakfast. Snack meals were positively associated with total energy intake in both groups. Conclusions: A new simplified method assessing meal pattern revealed that the number of reported intake occasions across a usual day was higher in obese women compared with controls and the timing was shifted to later in the day. These findings should be considered in the treatment of obesity. Sponsorship: Swedish Medical Research Council (27x-11653 and 19x-05239).

The aims of this study were to: describe dietary intakes of obese and nonobese middle‐aged women using a validated food frequency questionnaire; to assess dietary restraint, disinhibition, and hunger by the three factor eating questionnaire (TFEQ) in obese and nonobese samples and determine which of the factors are independently associated with obesity; and to examine correlations between selected nutritional variables and the TFEQ factors. Subjects studied included 179 obese Swedish women (BMI&gt;32) and 147 nonobese population‐based controls (BMI&lt;28). Age‐adjusted mean energy intake was significantly higher in obese women (2730 ± 78 vs. 2025 ± 85 kcal, p &lt;0.0001). In absolute and relative terms, fat intake was higher and alcohol intake was lower in the obese subjects. Disinhibition was the strongest TFEQ factor independently differentiating the obese and nonobese states, i.e., after adjustment for restraint and hunger. Within the obese sample, strong associations were seen between energy intake and disinhibition ( p =0.0005) and hunger ( p =0.0004). The association between energy intake and restrained eating was negative and weaker ( p =0.04). No such associations were seen in nonobese women. Thus, using a dietary instrument that is valid and unbiased with respect to obesity, strong psychological correlates, possibly causal, of variability in energy intake were detected in middle‐aged women with obesity. Disinhibition is associated with both obesity and high‐energy intakes and is therefore an important factor to consider in the treatment of women with obesity.

The authors considered whether the difference in body fat distribution between men and women, measured as waist:hip ratio, might explain part of the sex difference in coronary heart disease incidence in prospective population studies of 1,462 women and 792 men. In these studies, conducted in Sweden, men were found to have about four times higher odds for coronary heart disease than women during a 12-year follow-up period (men, 1967 to 1979; women, 1968-1969 to 1980-1981). Controlling for differences in blood pressure, serum cholesterol, smoking, and body mass index only marginally altered the magnitude of the male-female difference. When waist:hip ratio, which predicted coronary heart disease rates in both sexes, was also considered, the sex difference in coronary heart disease risk was significantly reduced and virtually disappeared (odds ratios = 1.0-1.1; nonsignificant). The findings suggest that body fat distribution or a factor highly correlated with waist:hip ratio (genetic, hormonal, or behavioral) may help to explain the sex differences in coronary heart disease.

The mean cell sizes of specimens of human adipose tissue were determined on sectioned slices according to the method described by Sjostrom et al. (J. Lipid Res. 1971. 12: 521-530) and on adipocytes isolated after treatment of the tissue with collagenase. The average mean cell sizes from 11 biopsy specimens were 94.4 and 94.0 micro m, respectively (r = 0.964; P(t(b)) < 0.001; y = 0.90x + 9.74), for the two methods. There was no indication of an increased rupture of isolated large human adipose cells. Thus, with precautions (freshly siliconized glassware and omitting the centrifugation of the isolated cells), the collagenase method may be used for metabolic as well as morphologic studies of human adipose tissue.

Abstract Objective: Associations between preproghrelin DNA variants and obesity‐related phenotypes were studied in 3004 subjects from the Québec Family Study (QFS), the HERITAGE Family Study (HERITAGE), and the Swedish Obese Subjects (SOS) Study. Research Methods and Procedures: Body mass index (BMI), fat mass (FM) from underwater weighing, and abdominal fat from computerized tomography were measured. The ghrelin polymorphisms were identified by polymerase chain reaction. Results: Arg51Gln QFS subjects ( n = 6) had lower ghrelin concentrations ( p = 0.007) than Arg51Arg subjects ( n = 14). White preproghrelin Met72Met subjects in HERITAGE had the lowest BMI ( p = 0.020), and those in the QFS cohort had the lowest FM ( p &lt; 0.001). Met72 carrier status (Met72+) was associated with lower FM ( p = 0.026) and higher insulin‐like growth factor‐1 levels ( p = 0.019) among blacks. Met72Met QFS subjects had less visceral fat ( p = 0.002) and a lower fasting respiratory quotient ( p = 0.037). HERITAGE Met72+ white subjects also showed lower exercise respiratory quotient ( p = 0.030) and higher maximal oxygen uptake ( p = 0.023). Furthermore, the prevalence of Met72+ was higher (19.2%; p &lt; 0.05) in SOS subjects whose BMI was ≤25 kg/m 2 than in those with BMI &gt;25 kg/m 2 (14.8%). SOS Met72+ obese women had a lower (11.4%; p = 0.032) prevalence of hypertension than noncarriers (23.9%). Discussion: Arg51Gln mutation was associated with lower plasma ghrelin levels but not with obesity. The preproghrelin Met72 carrier status seems to be protective against fat accumulation and associated metabolic comorbidities.

Abstract The aim of the present clinical trial was to test tolerability during 2 treatments with EMDOGAIN® in a large number of patients. An open, controlled study design in 10 Swedish specialist clinics was chosen, with a test group of 107 patients treated with EMDOGAIN® in connection with periodontal surgery at 2 surgical test sites per patient. The procedures were performed 2 to 6 weeks apart on one‐rooted teeth with at least 4 mm deep intraosseous lesions. A control group of 33 patients underwent flap surgery without EMDOGAIN® at I comparable site. In total 214 test and 33 control surgeries were performed. Serum samples were obtained from test patients for analysis of total and specific antibody levels. 10 of the patients had samples taken before and after the first surgery. 56 other samples were taken after one treatment with EMDOGAIN®, and 63 after 2 treatments. None of the samples, not even from allergy‐prone patients after 2 treatments, indicated deviations from established baseline ranges. This indicates that the immunogenic potential of EMDOGAIN® is extremely low when applied in conjunction with periodontal surgery. Comparison between the test and control groups demonstrated the same type and frequency of post‐surgical experiences, i.e., reactions caused by the surgical procedure itself. Clinical probing and radiographic evaluation was performed at baseline and 8 months postsurgery. About half of the patients (44 test and 21 control) were also evaluated after 3 years. There was a significant difference between the test and control results at 8 months post surgery. and this difference had increased further at the 3 year follow‐up. The 2.5–3 mm increase in attachment and bone level after treatment with EMDOGAIN® was of the same magnitude as seen in the studies with split‐mouth design aiming for lest of effectiveness of EMDOGAIN®.

All large prospective studies (n > 20 000) and several smaller studies have found that severe obesity [body mass index (BMI) ≥ 35 kg/m2] is associated with approximately a twofold increase in total mortality and in a severalfold increase in mortality due to diabetes, cerebro-, and cardiovascular disease, and certain forms of cancer. Studies that have not been able to confirm this have been small and/or short term, have failed to control for smoking or early mortality, have controlled for intermediate risk factors in an inappropriate way, or have a reduced internal validity due to misclassification biases. As compared with BMI, abdominal obesity is a stronger predictor of mortality in most studies available. The incidence of sudden death unexplained by autopsy may be up to 40 times higher in severely obese subjects as compared with the general population. A small weight increase since the age of 18 is associated with a decreased risk whereas weight increases > 10 kg are associated with an increased mortality. The total mortality ratio for severe obesity decreases from 55 y of age and is not detectable above 80 y of age. Studies lacking adequate control groups indicate that a sustained weight loss may induce a reduced mortality but results from controlled intervention studies are so far not available.

The main purpose of this trial was to determine the effects of 2 yr of GH treatment on bone mineral density (BMD) and bone metabolism in patients with adult-onset GH deficiency. Forty-four patients (24 men and 20 women; aged 23-66 yr) participated in a 2-yr open treatment trial with recombinant human GH. BMD was assessed with dual energy x-ray absorptiometry, and serum concentrations of osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), and carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) were measured. After 2 yr of GH treatment, the BMD increased in the lumbar spine L2-L4 by 3.8% [95% confidence interval (CI), 2.1-5.5], in the femoral neck by 4.1% (CI, 2.1-6.1) in the femoral trochanter by 5.6% (CI, 3.8-7.4) and in Ward's triangle by 4.9% (CI, 2.2-7.6) compared with baseline. Patients with a z-score (difference in SD from the mean of age- and sex-matched subjects) below -1 SD responded with the most marked BMD increment. The serum concentrations of osteocalcin, PICP, and ICTP remained higher throughout the 2 yr of treatment. Women demonstrated a more marked increase in total body BMD and a less pronounced initial increment in osteocalcin, PICP, and ICTP than men. Two years of GH treatment induced a sustained increase in overall bone remodeling activity, which resulted in a net gain in BMD that was more marked in those subjects with a low pretreatment z-score.

To investigate the consequences of longstanding obesity on left ventricular mass and structure and to examine the effects of weight loss on these variables.Cross sectional survey and controlled intervention study.City of Gothenburg and surrounding areas. Sweden.41 obese patients treated with weight reducing gastric surgery, 31 obese patients treated conventionally, and 43 non-obese subjects.Changes in left ventricular mass and relative wall thickness.Obese patients had higher blood pressure, greater left ventricular mass, and increased relative wall thickness than did matched non-obese control subjects. Obese subjects treated with gastric surgery had a substantial weight loss and a significant reduction in all variables when compared with conventionally treated obese subjects. Univariate and multivariate analysis of pooled data from the two groups of obese subjects showed that changes in relative wall thickness and left ventricular mass were more closely related to the change in weight than to the concomitant change in blood pressure.Structural heart abnormalities occurring in conjunction with obesity diminish after weight loss. The regression in these structural aberrations is better predicted by the weight loss than by the accompanying reduction in blood pressure. To prevent or improve abnormalities of heart structure in obese people, weight control should be the primary goal; it should be regarded as at least as important as regulating blood pressure.

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.

<h2>Abstract</h2> Body cell mass, body fat, and total number of fat cells were determined in young men and women. In addition, regional determinations of adipose tissue thickness, fat cell size, and fat cell number were also performed. The individuals studied were 11 male and 12 female medical students with a mean age of 22 yr. In order to avoid deviations from ideal body weights, the individuals were preselected by using anthropometric standards. The women had more body fat than the men, which was due to an increase in the total number of fat cells. Mean fat cell size did not differ significantly between sexes. The women had greater adipose tissue thickness than the men, which was primarily due to an increase in local fat cell number in all regions investigated (epigastric, hypogastric, femoral, and gluteal) except in the gluteal region, where the difference was mainly explained by larger fat cells in women. When expressed in per cent of maximum values, the intrasexual patterns of adipose tissue thickness and local fat cell number in different regions were similar in men and women, while the pattern concerning fat cell size was slightly different between the sexes. There were no differences between sexes in cholesterol, triglyceride, fasting blood sugar, or fasting insulin values. Middle-aged randomly selected men and women examined previously had a larger amount of body fat than the young men and women, respectively, examined in the present investigation. This difference in body fat with age was due to a larger mean fat cell size in the middle-aged populations, while there was no difference in total fat cell number.

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.

Body fat, fat cell size, and fat cell number were determined in a longitudinal study on 16 normal-weight infants during the age period 1–18 mo. The methods used included whole-body counting of 40K for determination of body fat and adipose tissue biopsies. A new method of calculation of body fat in infants is presented. No sex differences were found. Body fat expressed as per cent of body weight increased from 16.2% to 28.1%. From 1 to 12 mo of age the expansion of body fat was explained by an increase in fat cell size, while in the age period 12–18 mo it was mainly due to an increase in fat cell number. At 18 mo the fat cell size was the same as in 8-yr-old girls and 22-yr-old women (normal-weight females previously studied). The fat cell number at 18 mo, however, was far below the number at 8 yr of age, as well as the still higher number of the 22-yr-old women.

Effective primary care practice (PCP) treatments are needed for extreme obesity. The Louisiana Obese Subjects Study (LOSS) tested whether, with brief training, PCPs could effectively implement weight loss for individuals with a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 40 to 60.The LOSS, a 2-year (July 5, 2005, through January 30, 2008) randomized, controlled, "pragmatic clinical trial" trained 7 PCPs and 1 research clinic in obesity management. Primary outcome measure was year-2 percentage change from baseline weight. Volunteers (597) were screened and randomized to intensive medical intervention (IMI) (n = 200) or usual care condition (UCC) (n = 190). The UCC group had instruction in an Internet weight management program. The IMI group recommendations included a 900-kcal liquid diet for 12 weeks or less, group behavioral counseling, structured diet, and choice of pharmacotherapy (sibutramine hydrochloride, orlistat, or diethylpropion hydrochloride) during months 3 to 7 and continued use of medications and maintenance strategies for months 8 to 24.The mean age of participants was 47 years; 83% were women, and 75% were white. Retention rates were 51% for the IMI group and 46% for the UCC group (P = .30). After 2 years, the results were as follows: (1) among 390 randomized participants, 31% in the IMI group achieved a 5% or more weight loss and 7% achieved a 20% weight loss or more, compared with 9% and 1% of those in the UCC group. (2) The mean +/- SEM baseline observation carried forward analysis showed a weight loss of -4.9% +/- 0.8% in IMI and -0.2 +/- 0.3% in UCC. (3) Last observation carried forward analysis showed a weight loss of -8.3% +/- 0.79% for IMI, whereas UCC was -0.0% +/- 0.4%. (4) A total of 101 IMI completers lost -9.7% +/- 1.3% (-12.7 +/- 1.7 kg), whereas 89 UCC completers lost -0.4% +/- 0.7% (-0.5 +/- 0.9 kg); (P < .001 for all group differences). Many metabolic parameters improved.Primary care practices can initiate effective medical management for extreme obesity; future efforts must target improving retention and weight loss maintenance.clinicaltrials.gov Identifier: NCT00115063.

The prevalence of obesity among adolescents has increased and we lack effective treatments.To determine if gastric bypass is safe and effective for an unselected cohort of adolescents with morbid obesity in specialized health care.Intervention study for 81 adolescents (13-18 years) with a body mass index (BMI) range 36-69 kg m(-2) undergoing laparoscopic gastric bypass surgery in a university hospital setting in Sweden between April 2006 and May 2009. For weight change comparisons, we identified an adult group undergoing gastric bypass surgery (n=81) and an adolescent group (n=81) receiving conventional care.Two-year outcome regarding BMI in all groups, and metabolic risk factors and quality of life in the adolescent surgery group.Two-year follow-up rate was 100% in both surgery groups and 73% in the adolescent comparison group. In adolescents undergoing surgery, BMI was 45.5 ± 6.1 (mean ± s.d.) at baseline and 30.2 (confidence interval 29.1-31.3) after 2 years (P<0.001) corresponding to a 32% weight loss and a 76% loss of excess BMI. The 2-year weight loss was 31% in adult surgery patients, whereas 3% weight gain was seen in conventionally treated adolescents. At baseline, hyperinsulinemia (>20 mU l(-1)) was present in 70% of the adolescent surgery patients, which was reduced to 0% at 1 year and 3% at 2 years. Other cardiovascular risk factors were also improved. Two-thirds of adolescents undergoing surgery had a history of psychopathology. Nevertheless, the treatment was generally well tolerated and, overall, quality of life increased significantly. Adverse events were seen in 33% of patients.Adolescents with severe obesity demonstrated similar weight loss as adults following gastric bypass surgery yet demonstrating high prevalence of psychopathology at baseline. There were associated benefits for health and quality of life. Surgical and psychological challenges during follow-up require careful attention.

To evaluate the effect of bariatric surgery on sleep apnea symptoms and obesity-associated morbidity in patients with severe obesity. Prospective study. University hospitals and community centers in Sweden. We investigated the influence of weight loss surgery (n=1729) on sleep apnea symptoms and obesity-related morbidity using a conservatively treated group (n=1748) as a control. Baseline BMI in surgical group (42.2±4.4 kg/m2) and control group (40.1±4.6 kg/m2) changed −9.7±5 kg/m2 and 0±3 kg/m2, respectively, at 2-year follow-up. In the surgery group, there was a marked improvement in all obstructive sleep apnea (OSA) symptoms compared with the control group (P <0.001). Persistence of snoring (21.6 vs 65.5%, adjusted OR 0.14, 95% CI 0.10–0.19) and apnea (27.9 vs 71.3%, adjusted OR 0.16, 95% CI 0.10–0.23) were much less in the surgery group compared with controls. Compared with subjects with no observed apnea at follow-up (n=2453), subjects who continued to have or developed observed apnea (n=404) had a higher incidence of diabetes (adjusted OR 2.03, 95% CI 1.19–3.47) and hypertriglyceridemia (adjusted OR 1.86, 95% CI 1.07–3.25) but not hypertension (adjusted OR 1.09, 95% CI 0.65–1.83) or hypercholesterolemia (adjusted OR 0.91, 95% CI 0.53–1.58). Bariatric surgery results in a marked improvement in sleep apnea symptoms at 2 years. Despite adjustment for weight change and baseline central obesity, subjects reporting loss of OSA symptoms had a lower 2-year incidence of diabetes and hypertriglyceridemia. Improvement in OSA in patients losing weight may provide health benefits in addition to weight loss alone.

Twenty-eight obese women were divided after arbitrary statistical guidelines obtained from control studies into hyperplastic (increase in fat cell number) (n equal to 10), hypertrophic obesity (increase in average fat cell size) (n equal to 11), and a remaining group (n equal to 7). All these subjects were treated on an outpatient basis with an energy-reduced diet (1,100 kcal/day) until weight decrease failure occurred. The fat cells of the femoral and gluteal regions were larger than in the abdominal region in hypertrophic obese subjects. This regional fat cell size profile was found also in middle-aged and young controls. The hyperplastic obese subjects on the other hand had larger fat cells in the abdominal site. At failure of therapy enlarged fat cells in either of the two obesity groups had decreased to the size of fat cells of controls. Fat cell number remained unchanged. Thus the hypertrophic obese patients ended up with a normal body fat while hyperplastic obese subjects had a pronounced remaining obesity. The results suggest that when the fat cell size in different regions of an individual are known, as well as the total fat cell number, the success of an energy-reduced dietary regimen might be approximately predicted both in terms of remaining total body fat and in regional fat depot decrease.

Body fat, adipose tissue fat cell size and number, plasma lipids, and glucose tolerance with plasma insulin were determined in randomly selected middle-aged men and women and in young men. Body fat correlated with both fat cell size and number. The associations with fat cell size were apparently somewhat stronger than with fat cell number. Middle-aged women had higher body fat than middle-aged men, but no difference could be demonstrated in fat cell size or number. Subjects whose weight was stable were characterized by a normal number of small fat cells. In middle-aged men, fat cell size correlated with plasma insulin concentration. The latter in combination with decreased glucose tolerance was associated with increased plasma triglyceride concentration. In women, none of these associations were found.

Background Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3 I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n = 4047). Methods We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. Results A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value = 0.001), but not in the surgery group (log-rank P-value = 0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5–23.8; P-value = 0.013) of developing hepatocellular carcinoma was observed only in the control group. Conclusion The current study is the first prospective report showing the association of the PNPLA3 I148M genetic variant and hepatocellular carcinoma in severely obese individuals.

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.

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/- 3.4 kg/m(2)) and in 96 non-obese female controls (mean BMI 23.0 +/- 1.4 (kg/m2) of the Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg51Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p < 0.05). The self-reported weight at 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respectively, among obese Gln allele carriers versus obese non-carriers. In addition, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detected in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozygotes) subjects. This mutation outside the coding region of the mature ghrelin product tended to be associated with lower age of self-reported onset of obesity (15.6 +/- 7.9 vs. 20.5 +/- 10.5 years; p = 0.09). In addition to these two mutations in coding regions, a G274A base change in a non-coding region between exons one and two was found only in two obese individuals. The Arg51Gln amino acid substitution may alter the cleavage site of endoproteases and the length of the mature ghrelin product. The functional significance of the Leu72Met mutation and a G274A base change remains to be determined. In conclusion, the data provide evidence that a low frequency sequence variation in the ghrelin gene could play a role in the etiology of obesity.

Obese people frequently suffer from shortness of breath and chest discomfort on exertion, and they often have a sedentary lifestyle. In the present study of patients with severe obesity, we investigated the effects of surgically induced weight loss on cardiorespiratory symptoms and leisure-time physical activity.The Swedish Obese Subjects study is an ongoing intervention trial of obesity consisting of 1 surgically treated group and 1 matched control group. Information on smoking habits, hypertension, diabetes, and sleep apnea was obtained from 1210 surgical cases and 1099 controls who were observed for 2 years. Patients were also asked about symptoms of breathlessness and chest pain and their levels of leisure-time physical activity.The surgically treated group displayed a mean weight loss of 28 kg (23%) compared with the control group in which the average weight remained unchanged (P<.001). The rates of hypertension, diabetes, and apneas during sleep decreased in surgical cases compared with controls (P<.001), while smoking habits remained largely the same. The surgical group also displayed highly significant improvements in dyspnea and chest pain and increases in physical activity compared with the control group (P<.001). The odds ratio for self-reported breathlessness, chest discomfort, or sedentary behavior after 2 years decreased progressively with the degree of weight loss. Furthermore, patients who recovered from apneas during sleep reduced their odds of having dyspnea and chest discomfort at follow-up, independent of changes in weight.Surgically induced weight loss in patients with severe obesity is associated with a marked relief in symptoms of dyspnea and chest pain and promotes increased leisure-time physical activity. Sleep-disordered breathing may be involved in the pathophysiology of breathlessness and chest discomfort in obese subjects.

Obesity is associated with increased morbidity rates and pharmaceutical costs. To what extent various medication costs are affected by intentional weight loss is unknown.A cross-sectional comparison of the use of prescribed pharmaceuticals was conducted in 1286 obese individuals in the Swedish Obese Subjects (SOS) intervention study and 958 randomly selected reference individuals. Medication changes for 6 years after bariatric surgery were evaluated in 510 surgically and 455 conventionally treated SOS patients.Compared with the reference group, obese individuals were more often taking diabetes mellitus, cardiovascular disease, nonsteroidal anti-inflammatory and pain, and asthma medications (risk ratios ranging from 2.3-9.2). Average annual costs for all medications were 1400 Swedish kronor (SEK) (US $140) in obese individuals and 800 SEK (US $80) in the reference population (P<.001). Average yearly medication costs during follow-up were 1849 (US $185) in surgically treated patients (weight change -16%) and 1905 SEK (US $190) in weight-stable conventionally treated patients (P =.87). The surgical group had lower costs for diabetes mellitus (difference: -94 SEK/y (-US $9]) and cardiovascular disease medications (difference: -186 SEK/y (-US $19]) but higher costs for gastrointestinal tract disorder (difference: +135 SEK/y [US $13]) and anemia and vitamin deficiency medications (difference: +50 SEK/y [US $5]).Use and cost of medications are markedly increased in obese vs reference populations. Surgical obesity treatment lowers diabetes mellitus and cardiovascular disease medication costs but increases other medication costs, resulting in similar total costs for surgically and conventionally treated obese individuals for 6 years.

Obesity is associated with increased morbidity and mortality. Several observational epidemiological studies have indicated that weight gain and weight loss, even in the obese, is also related to an increased mortality. The Swedish Obese Subjects (SOS) study was initiated in 1987 as an attempt to elucidate this paradox.Two thousand matched patient pairs will be followed for 10 y each. One pair member is surgically treated, while the other receives conventional obesity treatment. By February 2000, 1879 patient pairs have been recruited.The two-y weight reduction was 28+/-15 kg among the operated patients and 0.5+/-8.9 kg among the obese controls. After eight years the weight loss was 20+/-16 kg in the surgical group, while the controls had gained 0.7+/-12 kg. Weight reductions achieved in the surgical group reduced the two-y incidence of diabetes 32 times as compared to the controls. After eight years there was still a 5-fold reduction in diabetes incidence. The two-y incidence of hypertension was similarly reduced 2.6 times in the surgical group. After eight years the incidence of hypertension was almost equal in the two study groups.Compared to weight stability, large intentional weight loss results in substantial reductions in the two-y incidence of several cardiovascular risk factors. After eight years there is still a reduced risk of developing diabetes in the surgical group, while the incidence of hypertension is equal in the two treatment groups. Whether intentional weight loss will reduce mortality is still too early to tell.

We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two first-degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1(<50% of the matched control group) was seen in «30% of both groups and these individuals were characterized by insulin resistance and its hallmarks: higher levels of insulin, glucose, and triglycerides. Two individuals with previously unknown NIDDM were diagnosed and both had low IRS 1 expression. Low IRS 1 protein expression was associated with low mRNA levels but not with the common Gly972Arg polymorphism of the IRS 1 gene. Taken together, our present and previous findings show that a low expression of IRS 1 in fat cells predicts insulin resistance and NIDDM. Furthermore, they support the likelihood that an impaired transcriptional activation may play a key role in the pathogenesis of NIDDM.—Carvalho, E., Jansson, P.-A., Axelsen, M., Eriksson, J. W., Huang, X., Groop, L., Rondinone, C., Sjostrom, L., Smith, U. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J. 13, 2173–2178 (1999)

The beta adrenergic system plays a key role in regulating energy balance through the stimulation of both thermogenesis and lipid mobilization in brown and white adipose tissues in human and various animal models. Recent studies have suggested that a missense Trp64Arg mutation in the beta3 adrenergic receptor (ADRB3) gene was involved in obesity and insulin resistance. We have investigated the effect of this mutation on obesity-related phenotypes in two cohorts: the Québec Family Study (QFS) and the Swedish Obese Subjects (SOS). In QFS, no association was found between this mutation and body mass index (BMI), body fat including abdominal visceral fat, resting metabolic rate, various diabetes and cardiovascular risk factors, and changes in body weight and body fat over a 12-yr period. With the exception of RMR (P = 0.04), no evidence of linkage was detected between the mutation and phenotypes of QFS based on sib-pair data. In SOS, the frequency of the Trp64Arg allele was not significantly different between nonobese and obese female subjects and no association was found between the mutation and body weight gain over time. These findings do not support the view that there is an association between the Trp64Arg mutation in the ADRB3 gene and obesity.

To investigate the extent of carotid artery atherosclerosis in obese subjects and to examine the possible effects of weight loss on atherosclerotic development.Controlled 4 y intervention study.20 obese patients treated with weight-reducing gastroplasty, 19 obese patients treated with dietary recommendations and 35 lean subjects.Body weight, blood pressure, blood lipids, glucose and insulin were measured. A B-mode ultrasound was recorded to determine the intima-media thickness (IMT) and lumen diameter (LD) of the carotid artery. Study groups were investigated at baseline and re-examined after 3 to 4 y of follow-up.At baseline, obese patients had higher blood pressure, serum total cholesterol, triglycerides, glucose and insulin compared with lean subjects; they also had a larger IMT in the carotid artery bulb (P<0.05) and a larger LD in the common carotid artery (P<0.01). After 4 y of follow-up, obese patients treated with surgery displayed a mean weight loss of 22 kg (19%), while the average weight in the obese control group remained unchanged (P<0.001). The weight loss group showed improvements in blood pressure, HDL-cholesterol, triglycerides and insulin compared with the obese control group (P<0.05). The progression rate of carotid bulb IMT in the weight loss group was similar to that observed in the lean control group (0.024 vs 0.025 mm/y, n.s.), whereas the IMT progression rate was almost three times higher in the obese control group (0.068 mm/y, P<0.05 compared with lean controls).Obese people have an unfavourable risk factor profile and signs of premature carotid artery atherosclerosis. Weight loss is followed by an improvement in several risk factors and may reduce the progression rate of atherosclerotic changes in the carotid artery bulb.

Recently we reported a complete relapse in the blood pressure (BP) of obese subjects despite a maintained 16% weight loss over 8 years. This relapse is now analyzed as a function of several variables. Pulse pressure (PP) is an independent risk factor of cardiovascular mortality. We now examine the development of PP in the obese and whether it can be modified by weight-reducing gastric surgery.A total of 1157 patients treated with gastric surgery and 1031 obese controls (body mass index of 41.0 +/- 4.6 kg/m(2) [mean +/- SD], age 48 +/- 6 years) were followed for 5.5 +/- 2.1 (range 3 to 10) years. To separate the effect of weight change from effect of time on BP, the patients were divided in cohorts based on follow-up time.Gastric surgery resulted in a maximum weight loss after 1 year that was followed by a moderate relapse. After 5.5 years, weight loss in the intervention group was 18 +/- 11% of initial body weight. Very little weight change was seen in controls. Systolic BP decreased in the intervention group during the first 6 months but had relapsed to control values at last examination. The adjusted change in PP was +4.7 mm Hg in obese controls but +2.9 mm Hg in the intervention group (p < 0.001). Final BP values were more closely related to follow-up time and ongoing weight increase than to initial body weight or initial weight loss.Effects of time (aging) and weight change per year on BP can be separated. An early increase in PP could be observed in the obese. This increase could be modified by weight-reducing gastric surgery.

Relationships between cardiovascular risk factors, body composition, and tissue distributions were examined in 10 Indian and 10 Swedish males matched by age, height, and weight. The body was divided into 29 compartments by means of a multiscan computed tomography (CT) technique. Fasting glucose, insulin, and triglycerides (TG) were higher in Indians than in Swedes. During the oral glucose tolerance test (OGTT), the glucose area was similar in both groups, whereas the insulin area was 80% larger in Indians. Adipose tissue (AT) and skin volumes were larger and remaining lean tissues were smaller in Indians. Indians had proportionally less muscle and more skeleton in the legs, but no ethnic difference could be demonstrated with respect to AT distribution. The visceral AT to total AT volume ratio was positively related to insulin and TG, and with higher risk factors for Indians at any given ratio. TG and glucose were negatively related to the leg muscle to total muscle volume ratio, and this ratio was smaller in Indians. It is concluded that the metabolic disturbances of Indians are not necessarily dependent on a preponderance of visceral AT, and also that an upper-body muscle distribution—recognized as a new phenotypic companion to the metabolic syndrome—is statistically related to cardiovascular risk factors.

Angiotensin II regulates blood pressure and may affect adipogenesis and adipocyte metabolism. Angiotensin II is produced by cleavage of angiotensinogen by renin and angiotensin-converting enzyme in the circulation. In addition, angiotensin II may be produced in various tissues by enzymes of the renin-angiotensin system (RAS) or the nonrenin-angiotensin system (NRAS). We have analyzed the expression of angiotensinogen and enzymes required for its conversion to angiotensin II in human adipose tissue. Northern blot demonstrated angiotensinogen expression in adipose tissue from nine obese subjects. Western blot revealed a distinct band of expected size of the angiotensinogen protein (61 kDa) in isolated adipocytes. RT-PCR, followed by Southern blot, demonstrated renin expression in human adipose tissue. Angiotensin-converting enzyme messenger RNA was detected by RT-PCR, and the identity of the PCR products was verified by restriction enzyme cleavage. Transcripts for cathepsin D and cathepsin G, components of the NRAS, were detected by RT-PCR, verified by restriction enzyme cleavage. We conclude that human adipose tissue expresses angiotensinogen and enzymes of RAS and NRAS. This opens the possibility that angiotensinogen-derived peptides, produced in adipose tissue itself, may affect adipogenesis and play a role in the pathogenesis of obesity.

The most central findings in both GH deficiency in adults and the metabolic syndrome are abdominal/visceral obesity and insulin resistance. Abdominal obesity is associated with blunted GH secretion and low serum insulin-like growth factor-I concentrations. GH treatment in GH-deficient adults has demonstrated favorable effects on most of the features of GH deficiency in adults, but it is not known whether GH can improve some of the metabolic aberrations observed in abdominal/visceral obesity. Thirty men, 48-66 yr old, with abdominal/visceral obesity were treated with recombinant human GH (rhGH) in a 9-month randomized, double-blind, placebo-controlled trial. The daily dose of rhGH was 9.5 micrograms/kg. Body fat was assessed from total body potassium, and abdominal sc and visceral adipose tissue was measured using computed tomography. The glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp. In response to the rhGH treatment, total body fat and abdominal sc and visceral adipose tissue decreased by 9.2 +/- 2.4%, 6.1 +/- 3.2%, and 18.1 +/- 7.6%, respectively. After an initial decrease in the GDR at 6 weeks, the GDR increased in the rhGH-treated group as compared with the placebo-treated one (P < 0.05). The mean serum concentrations of total cholesterol (P < 0.01) and triglyceride (P < 0.05) decreased, whereas blood glucose and serum insulin concentrations were unaffected by the rhGH treatment. Furthermore, diastolic blood pressure decreased and systolic blood pressure was unchanged in response to rhGH treatment. This trial has demonstrated that GH can favorably affect some of the multiple perturbations associated with abdominal/visceral obesity. This includes a reduction in abdominal/visceral obesity, an improved insulin sensitivity, and favorable effects on lipoprotein metabolism and diastolic blood pressure.

The purpose of this study was to investigate whether upper body obesity and/or visceral obesity are related to cardiovascular risk factors among severely obese subjects, phenomena that have previously been reported in more heterogeneous body weight distributions. 2450 severely obese men and women aged 37 to 59 years, with a body mass index of 39 +/- 4.5 kg/m2 (mean +/- SD) were examined cross-sectionally. Eight cardiovascular risk factors were studied in relation to the following body composition indicators: four trunk and three limb circumferences, along with weight, height and sagittal trunk diameter. From the latter three measurements lean body mass (LBM, i.e., the non-adipose tissue mass) and the masses of subcutaneous and visceral adipose tissue were estimated by using sex-specific prediction equations previously calibrated by computed tomography. Two risk factor patterns could be distinguished: 1. One body compartment-risk factor pattern in which the subcutaneous adipose tissue (AT) mass and, in particular, the visceral AT mass were positively related to most risk factors while the lean body mass was negatively related to some risk factors. 2. One subcutaneous adipose tissue distribution- risk factor pattern in which the neck circumference was positively and the thigh circumference negatively related to several risk factors. It is concluded that lean body mass (LBM), visceral and subcutaneous adipose tissue masses as well as neck and thigh circumferences, used as indices of subcutaneous adipose tissue distribution, are independently related to cardiovascular risk factors in severely obese men and women.

OBJECTIVES: To analyse sick leave and disability pension among surgically and conventionally treated obese patients. DESIGN: A prospective study over five years. Differences in sick leave and disability pension were analysed using multiple and logistic regressions. Possible confounding factors were analysed and controlled for. SETTING: Nine counties in Sweden. SUBJECTS: 369 surgically treated patients and 371 matched obese controls, included in the Swedish Obese Subjects (SOS) study. At baseline, mean body mass index (BMI) was 42 kg/m2 in surgical patients and 41 kg/m2 in controls. After four years of treatment, weight reduction was 20% among surgical patients while the control patients kept their initial weight. INTERVENTION: Gastric bariatric surgery. MEASUREMENTS: Days of sick leave plus disability pension, and days of disability pension. RESULTS: In the year prior to treatment, adjusted average number of days of sickness due to sick leave plus disability pension was similar in surgical patients and controls. Compared with controls, the surgical group had 35% more days of sickness during the first year after initiation of treatment, but 10–14% fewer days during years 2–3. During year four, days of sickness tended to be lower in the surgical group (P=0.07). In the sub-group, aged above the median, surgical patients had 14–18% fewer days of sickness than controls, during years 2–3 after initiation of treatment This difference did not occur in the group below median age. CONCLUSION: Surgical treatment of obesity results in a reduction of sick leave and disability pension, compared to controls, particularly in subjects aged 47–60 y.

The prevalence of mutations within and in the flanking regions of the gene encoding the melanocortin 4 receptor was investigated in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and nine novel (three missense, six silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, two novel deletions were found in two heterozygous obese women: a -65_-64delTG mutation within the 5' noncoding region and a 171delC frameshift mutation predicted to result in a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. In conclusion, our results do not support the prevailing notion that sequence variation in the melanocortin 4 receptor gene is a frequent cause of human obesity.

Twenty-five obese and 23 reference women were compared with respect to their peripheral insulin concentrations in response to the sight and smell of food. An additional 21 obese women were examined for different control purposes. The women were examined after fasting for approximately 16 hr. Venous blood samples for determination of glucose and insulin were drawn 20, 10, and 1 min prior to the demonstration of food for 5 min. After the food had been presented to the subjects, samples were drawn at 1, 2, 3, 4, 5, 6, 10, 15, and 20 min. The response was calculated in two different ways: method I--the difference between meal basal insulin values and mean insulin values during and/or after stimulation, and method II--the "insulin area" over the mean basal concentration was calculated for 0-20 min after start of food presentation. Both methods resulted in significantly higher insulin responses in obese as compared to reference subjects. However, when performing duplicate experiments in the same subjects only method II resulted in reproducible results and even with this method the error was as high as 60%-90%. The high error of the method was partly expected since the insulin elevation is most likely not only a function of controlled external cues but also dependent on unknown sensorimotor and cognitive-affective alterations. No insulin response was observed when obese women were exposed to an external cue that was not food related. Atropine completely blocked the insulin elevation in response to food related external stimuli indicating that this insulin response is mediated via vagus.

Sixty moderately obese women (mean BMI = 33, mean age = 43), randomized to a lactovegetarian or regular 1300-kcal weight-reducing diet were followed at 3, 8 and 24 months. Weight follow-up was 92%, while 47% complied with the program throughout with no differences between the two diets with respect to compliance rate, weight loss or behavioral test results. Over 24 months compliers lost a mean 3.9 kg compared to a gain of 1.8 kg in the non-compliers. Short-term improvements in mental well-being measured by the Mood Adjective Check List deteriorated after 2 years to lower levels than at entry. Self-assessed motivation to diet was inversely related to mental well-being at two years. Positive long-term changes of functional status (Sickness Impact Profile) were found. Though subjective prediction of success measured after 3 weeks on diet predicted short-term and maximum weight loss, it did not predict ultimate outcome. More difficulties in resisting emotional and social eating cues (high disinhibition score on the Three-Factor Eating Questionnaire) before and during the diet predicted weight gain. The more initial health-related dysfunction (SIP) the greater the weight regain. Psychological characteristics at baseline did not predict compliance or overall weight loss. The magnitude of weight loss after 24 months was related to amount and duration of maximum weight 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.

Body composition and total number of fat cells were investigated in 31 randomly selected women 52 yr of age and in 13 young women (mean age 22 yr) whose body weights were within ±10% of the ideal weight. Two of the 52-yr-old women were obviously obese and excluded. Regional determinations of adipose tissue thickness, fat cell size, and number were also determined. Middleaged women had more body fat (BF) but a lower body cell mass (BCM) than the younger group. The increased BF in the middle-aged women was exclusively explained by larger fat cells, since the younger women had a significantly higher total number of fat cells. This increase was also found when differences in height, body weight, and body fat were matched out. Local fat cell number was also increased in the younger group. Local fat cell size was increased in all regions investigated in the middle-aged women, but the increase was particularly pronounced in the abdominal region. The highest degrees of correlation between fat cell sizes of different regions were found between the epigastric and hypogastric regions and between femoral and gluteal regions. Furthermore, the plasma insulin levels correlated with the fat cell sizes of the abdominal region but not with those of the femoral or gluteal regions. In conclusion, the data might indicate that the fat cells of the abdominal region are more sensitive to nutritional and/or hormonal factors than those of other regions. This may in turn indicate the existence of different fat cell populations.

Abstract. Fat cells of different sizes were isolated from the same sample of adipose tissue by collagenase treatment and fractionation by flotation in an isoosmolar medium. Protein, phospholipid and cholesterol increased with increasing fat cell size. Cholesterol correlated most closely with fat cell volume but phospholipid apparently with surface. Most of fat cell cholesterol was found in the triglyceride droplet, and only a smaller part in a particulate fraction from fat cells. Incorporation of labelled glucose into triglyceride increased with fat cell size, apparently in proportion to fat cell surface rather than diameter or volume. This was the case also with incorporation into fatty acids. The association between fat cell size and metabolism was present also in alloxan diabetic rats. Short term insulin deficiency thus does not abolish the increase of metabolic activity with fat cell size. Analyses of activities of selected glycolytic enzymes and of fatty acid synthesis from acetate in cell‐free systems showed a similar dependence on fat cell size, demonstrating that isotope dilution phenomena in large and small fat cells are probably not responsible. — Lipolytic activity in the basal state and after epinephrine stimulation was increased in large fat cells, which also reesterified more fatty acids than small fat cells when calculated according to the balance method. — It was concluded that larger fat cells are metabolically more active than smaller fat cells. The increase of glyceride‐glycerol labelling and of glycerol release from larger fat cells suggests an increased triglyceride turn‐over in these fat cells. Large fat cells might thus be considered as an active metabolic sub‐compartment of adipose tissue.

Abstract. Body composition, age at onset of obesity, adipose tissue cellularity and metabolic variables have been determined in 137 obese subjects and controls. Weight stability in 34 of the patients could also be judged by a repeated examination after about 10 months. Fat cell number correlated strongly with body fat, while fat cell size increased only within the control range of body fat. Above approximately 30 kg body fat, the fat cell enlargement was equally pronounced at all degrees of obesity. A cross‐sectional analysis of the obese men and women indicated that fat cell size was larger at 30–40 years of age than before and after this age. Cell number was elevated but did not increase with age in the obese group. Groups of younger and older obese women did not differ in adipose tissue cellularity factors. This had the consequence that, in comparisons with age‐ and sex‐matched control groups, obesity depending primarily on enlargement of fat cells seemed to be more frequent in the younger age groups, while in older obese subjects cell number seemed to be a more important factor for contribution to obesity. Fat cell number correlated positively with body cell mass. The earlier the onset of obesity the more fat cells, particularly when obesity could be traced to infancy. Obesity starting at adult age was characterized by larger fat cells. Two types of obesity can be distinguished. One is a hypercellular severe obesity with an early onset and an elevated body cell mass. The fat cells may be enlarged or not. The other type of obesity is characterized by fat cell hypertrophy, moderately increased body fat and a later onset. There is no increase in body cell mass. Plasma insulin was dependent on weight stability. Hypertriglyceridemia in obesity was associated with a decreased glucose tolerance, somewhat elevated insulin values, and elevated serum uric acid.

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.

Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI ⩾ 34 in men and BMI ⩾ 38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years.During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P < 0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.

Patients with severe obesity commonly have obstructive sleep apnea (OSA). In order to determine the impact of OSA on psychosocial morbidity in severe obesity, subjects enrolled in the Swedish Obese Subjects (SOS) Study were classified into two subgroups based on questionnaire data: one group with a high likelihood and one with a low likelihood of OSA. These groups were contrasted and multivariable analysis was used to examine whether OSA had independent effects on divorce rate, sick leave, work performance, income and self-estimated general health after adjustment for obesity, fat distribution, alcohol, smoking, medications and coexisting medical conditions. A high likelihood of OSA was identified in 338 men and 155 women, compared with 216 men and 481 women who had a low likelihood of OSA. Men with OSA were identical in age to men without OSA and had slightly higher levels of visceral fat (p = 0.01), but were similar in most psychosocial variables except self-perceived general health. Women with OSA were identical in age and visceral fat mass to women without OSA, but were characterized by a higher rate of impaired work performance, sick leave and divorce. When frequent sleepiness was used as an additional discriminator between OSA and non-OSA groups, marked differences in psychosocial morbidity were observed. Multivariable analysis revealed either OSA or frequent sleepiness or both to be independent predictors of amount of sick leave, worse self-rated general health, impaired work performance and divorce rate. Therefore OSA, measured by self report, is an important independent predictor of psychosocial morbidity in subjects with severe obesity.

Longitudinal studies on changes in body composition and adipose tissue (AT) distribution in response to altered cortisol exposure have not yet been undertaken. Therefore, we determined body composition in seven women aged 34 +/- 9 years (mean +/- SD) with Cushing's disease/syndrome before and 8 +/- 2 (SD) months after surgical treatment for pituitary (n = 5) or cortical adrenal (n = 2) adenomas. The treatment resulted in a reduction of plasma and urinary cortisol by 78% and 97% (P < .01), respectively, and body weight (BW) reductions of 10.2 +/- 8.1 (SD) kg. The volumes of AT, skeletal muscle plus skin, and visceral organs were determined using a multiscan computed tomography (CT) technique. Organ and tissue volumes were converted to weight by multiplying with organ densities. After treatment, AT was reduced by 8.2 +/- 6.1 kg (P = .012), skeletal muscle plus skin by 1.3 +/- 1.7 kg (NS), and visceral organs by 0.6 +/- 1.0 kg (NS). The net change of AT, skeletal muscle plus skin, and visceral organs (delta AMV) was thus -10.1 +/- 7.8 kg, which was in good agreement with the change in BW (delta BW, -10.2 +/- 8.1 kg). The standard error of a single determination calculated on the differences between delta BW and delta AMV was 2.8%. Although total skeletal muscle plus skin was not changed, muscle of arms was reduced by 0.3 +/- 0.2 L (P = .014). Except for leg AT (P = .088), the reductions of all regional AT depots (arms, head+neck, subcutaneous trunk, viscera) were significant when expressed in liters. The total AT was reduced by 23% +/- 11%.(ABSTRACT TRUNCATED AT 250 WORDS)