CiteULike: omalbam's obesity

High Prevalence of Central Adrenal Insufficiency in Patients with Prader-Willi Syndrome

de Lind — 2008-05-11T23:51:05-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1649-1654.

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. Setting: The study was conducted in a pediatric intensive care unit. Patients: Patients included 25 randomly selected PWS patients. Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. Conclusions: Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test. 10.1210/jc.2007-2294

Whole Grain Consumption and Body Mass Index in Adult Women: An Analysis of NHANES 1999-2000 and the USDA Pyramid Servings Database

Carolyn Good — 2008-05-06T19:57:55-00:00

J Am Coll Nutr, Vol. 27, No. 1. (1 February 2008), pp. 80-87.

Objective: To examine the relationship between whole grain consumption and body mass index (BMI) in a sample of American adult women. Methods: Dietary intake data from the National Health and Nutrition Examination Survey 1999-2000 were linked to the USDA Pyramid Servings Database. Women 19 years of age and older (n = 2,092) were classified into groups based on their average whole grain (WG) intake: 0 servings, more than 0 but less than 1 serving, and [≥]1 servings per day. Within these classifications, mean BMI, mean waist circumference and percent overweight/obese (BMI [≥] 25) were identified as primary dependent variables. Regression and logistic regression analyses were used to assess associations between BMI, waist circumference and percent of the population overweight/obese (BMI [≥]25) and WG consumption. Results: Women consuming at least one serving of WG had a significantly lower mean BMI and waist circumference than women with no WG consumption (p < 0.05). Multiple regression analysis showed a significant inverse relationship between BMI and whole grain intake after adjustment for age, energy intake, dietary fiber and alcohol intake (p = 0.004). This effect was mildly attenuated but remained significant after further adjustment for level of physical activity, smoking status, ethnicity and education (p = 0.018). The odds ratio for having a BMI [≥] 25 was 1.47 (95% CI 1.12-1.94; p for trend 0.013) for women consuming no WG compared to those consuming at least one serving, after adjustment for all covariates. Conclusions: These data support other research suggesting increased WG intake may contribute to a healthy body weight in adult women.

Variations in the uncoupling protein-3 gene are associated with specific obesity phenotypes

Annet van Abeelen — 2008-04-21T19:09:45-00:00

Eur J Endocrinol, Vol. 158, No. 5. (1 May 2008), pp. 669-676.

ObjectiveUncoupling protein 3 (UCP-3) uncouples oxidative metabolism from ATP synthesis, resulting in the production of heat instead of energy storage. Single nucleotide polymorphisms (SNPs) in UCP-3 might result in a reduced function or expression of UCP-3 and therefore lead to an increased capacity to store energy as fat. DesignWe conducted a population-based, cross-sectional single-center study among 400 Dutch men between 40 and 80 years. MethodsSeven SNPs in the UCP-3 gene were genotyped by means of an allele-specific real-time TaqMan PCR. Linear regression analyses were performed to examine the independent effects of these SNPs on obesity phenotypes. ResultsWe found a significant association between homozygosity for the minor allele of rs647126, rs1685356, and rs2075577 and an increase in body mass index (BMI; P=0.033, P=0.016, and P=0.019 respectively). Heterozygosity for rs1685354 was associated with a significant decrease in visceral fat mass (P=0.030). ConclusionsOur results suggest that genetic variations in the UCP-3 gene are associated with an increase in BMI. A plausible mechanism by which these SNPs lead to an increase in BMI is that due to these SNPs, the UCP-3 activity might be decreased. As a result, uncoupling activity may also decrease, which will lead to an increase in body weight and BMI. 10.1530/EJE-07-0834

Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

Robin Christensen — 2008-02-18T04:17:32-00:00

The Lancet, Vol. 370, No. 9600., pp. 1706-1713.

SummaryBackground Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.Methods We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.Findings Patients given rimonabant had a 4[middle dot]7 kg (95% CI 4[middle dot]1-5[middle dot]3 kg; p<0[middle dot]0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1[middle dot]4; p=0[middle dot]0007; number needed to harm=25 individuals [95% CI 17-58]), and 1[middle dot]4 times more serious adverse events (OR=1[middle dot]4; p=0[middle dot]03; number needed to harm=59 [27-830]). Patients given rimonabant were 2[middle dot]5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2[middle dot]5; p=0[middle dot]01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3[middle dot]0; p=0[middle dot]03; number needed to harm=166 [47-3716]).Interpretation Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety--despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results.

LM Ruilope — 2008-04-15T20:30:25-00:00

Journal of hypertension, Vol. 26, No. 2. (February 2008), pp. 357-367.

OBJECTIVE: Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme. METHODS: RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment. RESULTS: After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%). CONCLUSIONS: Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial.

LP Svetkey — 2008-04-07T17:50:47-00:00

JAMA : the journal of the American Medical Association, Vol. 299, No. 10. (12 March 2008), pp. 1139-1148.

CONTEXT: Behavioral weight loss interventions achieve short-term success, but re-gain is common. OBJECTIVE: To compare 2 weight loss maintenance interventions with a self-directed control group. DESIGN, SETTING, AND PARTICIPANTS: Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. INTERVENTIONS: After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology-based intervention, or self-directed control. Main Outcome Changes in weight from randomization. RESULTS: Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, -1.5 kg; 95% confidence interval [CI], -2.4 to -0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology-based (5.2 kg) and self-directed groups (5.5 kg; mean difference -0.3 kg; 95% CI, -1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology-based than in the self-directed group at 18 months (mean difference, -1.1 kg; 95% CI, -1.9 to -0.4 kg; P = .003) and at 24 months (mean difference, -0.9 kg; 95% CI, -1.7 to -0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology-based group was -1.2 kg (95% CI -2.1 to -0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. CONCLUSIONS: The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive technology-based intervention provided early but transient benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054925.

The Association Between the FTO Gene and Fat Mass in Humans Develops by the Postnatal Age of Two Weeks.

Abel López-Bermejo — 2008-02-18T16:12:09-00:00

J Clin Endocrinol Metab (5 February 2008)

Objective: Little is known about the genetic determinants of fat mass around birth. We hypothesized that the common rs9939609 single nucleotide polymorphism (SNP) in FTO is associated with fat mass and metabolic parameters in neonates. Design: Cross-sectional, hospital-based study. Patients: Two hundred and thirty-four full-term, healthy newborns [122 girls and 112 boys; gestational age (mean, range): 39.0 (37.0-42.0) w, birth weight: 3.2 (1.9-4.2) Kg]. Methods: Cord-blood insulin, IGF-I, IGFBP-1, adiponectin and visfatin, measured by specific immunoassays. Body composition, assessed by dual energy X-ray absorptiometry at approximately 13 d (range, 9-20 d). Genotyping of rs9939609 by retriction fragment length polymorphism analysis. Results: The rs9939609 SNP in FTO was not associated with birth weight; however it was associated with serum visfatin (p<0.001), with weight and ponderal index at age 2 weeks (p<0.05), and with total, truncal and abdominal fat (p<0.05 to p=0.01), so that AA homozygotes had 37% higher plasma visfatin concentration and 17%, 20% and 17% higher total, truncal and abdominal fat mass, respectively, than T-carrier neonates. Conclusion: Our findings support a role of the common rs9939609 SNP in FTO gene in the early stages of fat accretion in humans, and disclose novel associations between this SNP and both serum visfatin and abdominal fat mass in neonates.

Adipocyte prolactin: regulation of release and putative functions

Brandebourg — 2007-06-25T17:27:50-00:00

Diabetes, Obesity and Metabolism, Vol. 9, No. 4. (July 2007), pp. 464-476.

Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone.

B Zumoff — 2008-01-31T19:33:02-00:00

Metabolism, Vol. 52, No. 9. (September 2003), pp. 1126-1128.

Studies from this laboratory have shown that obese men have elevated serum estrogen levels and diminished levels of follicle-stimulating hormone (FSH) and free and total testosterone, all in proportion to their degree of obesity. The decreases in testosterone and FSH constitute a state of hypogonadotropic hypogonadism (HHG), and we have hypothesized that it results from feedback suppression of the pituitary by the elevated estrogen levels. We tested this hypothesis by lowering the serum estrogens of 6 health obese men (body mass index [BMI], 38 to 73) by administering the aromatase inhibitor testolactone (1 g daily for 6 weeks). Twenty-four-hour mean serum testosterone rose in every subject, from a mean of 290 +/- 165 ng/dL to a mean of 403 +/- 170 (P <.0003); 24-hour mean serum estradiol decreased in every subject, from a mean of 40 +/- 10.8 pg/mL to a mean of 29 +/- 6.7 (P <.004); and 24-hour mean serum luteinizing hormone (LH) increased in every subject, from a mean of 14.3 +/- 4.1 mIU/mL to a mean of 19.3 +/- 5.1 (P <.004). The rise in mean LH was due to an increase in the amplitude of the individual secretory pulses, especially at night. Twenty-four-hour mean serum estrone decreased nonsignificantly, from 48 +/- 14 pg/mL to 39 +/- 6.4, and 24-hour mean serum FSH increased nonsignificantly, from 13.5 +/- 5.3 mIU/mL to 15.0 +/- 5.4. The results are in accordance with the hypothesis, in that inhibition of estrogen biosynthesis (through administration of the aromatase inhibitor testolactone) results in alleviation of the HHG of our obese male subjects.

Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism

H de Boer — 2005-04-13T12:04:45-00:00

Diabetes, Obesity and Metabolism, Vol. 7, No. 3. (May 2005), pp. 211-215.

Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.

LK Heilbronn — 2007-08-29T10:03:01-00:00

JAMA, Vol. 295, No. 13. (5 April 2006), pp. 1539-1548.

CONTEXT: Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans. OBJECTIVE: To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La. INTERVENTION: Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). MAIN OUTCOME MEASURES: Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature. RESULTS: Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005). CONCLUSIONS: Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00099151.

Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance

P Sjögren — 2008-01-24T20:57:17-00:00

Diabetologia, Vol. 51, No. 2. (1 February 2008), pp. 328-335.

Abstract Aims/hypothesis Fatty acid desaturases introduce double bonds into growing fatty acid chains. The key desaturases in humans are Δ5-desaturase (D5D), Δ6-desaturase (D6D) and stearoyl-CoA desaturase (SCD). Animal and human data implicate hepatic desaturase activities in insulin resistance, obesity and dyslipidaemia. However, the role of desaturase activity in adipose tissue is uncertain. We therefore evaluated relationships between adipose mRNA expression, estimated desaturase activities (fatty acid ratios) in adipose tissue and insulin resistance. Methods Subcutaneous adipose tissue mRNA expression of D5D (also known as FADS1), D6D (also known as FADS2) and SCD was determined in 75 individuals representative of the study population of 294 healthy 63-year-old men. Desaturation indexes (product/substrate fatty acid ratios) were generated from adipose tissue fatty acid composition in all individuals. Insulin resistance was defined as the upper quartile of the updated homeostasis model assessment (HOMA-2) index. Results The relevant desaturation indexes (16:1/16:0, 18:1/18:0, 20:4/20:3 and 18:3/18:2) reflected expression of SCD, but not of D5D or D6D in adipose tissue. Insulin-resistant individuals had a higher adipose tissue 18:1/18:0, but not 16:1/16:0 ratio than insulin-sensitive individuals. Individuals with a high adipose tissue 18:1/18:0 ratio were 4.4-fold (95% CI 1.8–11.8) more likely to be insulin resistant [threefold (95% CI 1.1–8.6) after adjustment for waist circumference and plasma triacylglycerol]. In a multiple regression model predicting HOMA-2, the independent effect of the 18:1/18:0 ratio was borderline (p = 0.086). Conclusions/interpretation Adipose tissue desaturation indexes of SCD reflect the expression of the gene encoding the enzyme in this tissue. Elevated SCD activity within adipose tissue is closely coupled to the development of insulin resistance.

Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients

I Jazet — 2008-01-24T20:50:41-00:00

Diabetologia, Vol. 51, No. 2. (1 February 2008), pp. 309-319.

Abstract Aims/hypothesis Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients. Methods A euglycaemic–hyperinsulinaemic clamp with stable isotopes ([6,6-2H2]glucose and [2H5]glycerol) combined with skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively. Results Loss of 50% EWR (20.3 ± 2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8 ± 2.0 to 39.1 ± 2.8 μmol kg fat-free mass−1 min−1, p = 0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content. Conclusions/interpretation Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect.

Impact of Obesity on the Risk for Polycystic Ovary Syndrome

Bulent Yildiz — 2008-01-11T00:34:54-00:00

J Clin Endocrinol Metab, Vol. 93, No. 1. (1 January 2008), pp. 162-168.

Context: Although it is well established that adiposity increases the severity of the clinical features of polycystic ovary syndrome (PCOS), the data regarding the prevalence of PCOS in obese women and the change in body weight women presented with PCOS over time are scarce. Objective: The objective of the study was to determine whether obesity increases the risk of PCOS and whether the degree of obesity of PCOS patients has increased, paralleling the rise in obesity in the population. Design: We analyzed data from two consecutive populational studies assessing the prevalence of PCOS and a database containing all untreated PCOS patients evaluated at a university clinic between 1987 and 2002. Setting: The study was conducted at a tertiary care center. Patients or Other Participants: Participants included 675 women who participated in prevalence studies and 746 PCOS patients. Main Outcome Measures: Populational prevalence of PCOS according to body mass index (BMI) and change in BMI of PCOS patients over time were measured. Results: The prevalence rates of PCOS in underweight, normal-weight, overweight, and obese women were 8.2, 9.8, 9.9, and 9.0%, respectively. Prevalence rates reached 12.4 and 11.5% in women with BMI 3540 kg/m2 and greater than 40 kg/m2 (P = NS). The mean BMI of PCOS patients diagnosed between 1987 and 2002 rose, beginning in 1997 and reaching 37.3 +/- 9.9 kg/m2 in 20002002, paralleling the change in BMI of the surrounding population (1014% obesity rate in 1987, 1519% in 1997, and 25% or greater in 2002). Conclusion: Our results suggest that the risk of PCOS is only minimally increased with obesity, although the degree of obesity of PCOS patients has increased, similar to that observed in the general population. These data indicate that obesity in PCOS reflects environmental factors to a great extent. 10.1210/jc.2007-1834

The Acyclic CB1R Inverse Agonist Taranabant Mediates Weight Loss by Increasing Energy Expenditure and Decreasing Caloric Intake.

C Addy — 2008-01-09T16:07:29-00:00

Cell Metab, Vol. 7, No. 1. (January 2008), pp. 68-78.

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

Long-term mortality after gastric bypass surgery.

TD Adams — 2008-01-08T23:03:29-00:00

N Engl J Med, Vol. 357, No. 8. (23 August 2007), pp. 753-761.

BACKGROUND: Although gastric bypass surgery accounts for 80% of bariatric surgery in the United States, only limited long-term data are available on mortality among patients who have undergone this procedure as compared with severely obese persons from a general population. METHODS: In this retrospective cohort study, we determined the long-term mortality (from 1984 to 2002) among 9949 patients who had undergone gastric bypass surgery and 9628 severely obese persons who applied for driver's licenses. From these subjects, 7925 surgical patients and 7925 severely obese control subjects were matched for age, sex, and body-mass index. We determined the rates of death from any cause and from specific causes with the use of the National Death Index. RESULTS: During a mean follow-up of 7.1 years, adjusted long-term mortality from any cause in the surgery group decreased by 40%, as compared with that in the control group (37.6 vs. 57.1 deaths per 10,000 person-years, P<0.001); cause-specific mortality in the surgery group decreased by 56% for coronary artery disease (2.6 vs. 5.9 per 10,000 person-years, P=0.006), by 92% for diabetes (0.4 vs. 3.4 per 10,000 person-years, P=0.005), and by 60% for cancer (5.5 vs. 13.3 per 10,000 person-years, P<0.001). However, rates of death not caused by disease, such as accidents and suicide, were 58% higher in the surgery group than in the control group (11.1 vs. 6.4 per 10,000 person-years, P=0.04). CONCLUSIONS: Long-term total mortality after gastric bypass surgery was significantly reduced, particularly deaths from diabetes, heart disease, and cancer. However, the rate of death from causes other than disease was higher in the surgery group than in the control group.

11beta-HSD Type 1 Expression in Human Adipose Tissue: Impact of Gender, Obesity, and Fat Localization

Soren Paulsen — 2008-01-08T22:18:43-00:00

Obesity, Vol. 15, No. 8. (1 August 2007), pp. 1954-1960.

Objective: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the metabolic syndrome. Our objective was to compare 11beta-HSD1 gene expression in different fat depots (visceral, subcutaneous abdominal, and subcutaneous gluteal) in lean and obese men and women. Research Methods and Procedures: A cross-sectional study design was used for healthy patients undergoing minor abdominal surgery (lean men, 10), minor gynecological surgery (lean woman, 10), or gastric banding operations (obese men, 10; and obese women, 10). Gene expressions of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results: Lean women had lower 11beta-HSD1 gene expression in subcutaneous adipose tissue compared with men (62% lower, p < 0.01), whereas no significant difference was found between obese men and women. 11beta-HSD1 mRNA in human adipose tissue was higher in obese subjects compared with lean subjects in both women and men and in both subcutaneous and visceral adipose tissue. No difference in mRNA expression of 11beta-HSD1 between visceral and subcutaneous adipose tissue or between subcutaneous adipose tissue from different depots was found. Conclusions: 11beta-HSD1 in adipose tissue is increased in obesity in both women and men, and may contribute to the associated metabolic syndrome. As 11beta-HSD1 expression in lean women was found to be significantly lower than in lean males, the up-regulation associated with obesity may be relatively more devastating in women than in men, and may help explain the higher relative risk of cardiovascular disease in women suffering from the metabolic syndrome.

Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain: A Randomized Controlled Trial

Ren Wu — 2008-01-08T22:11:10-00:00

JAMA, Vol. 299, No. 2. (2008), pp. 185-193.

Context Weight gain, a common adverse effect of antipsychotic medications, is associated with medical comorbidities in psychiatric patients. Objective To test the efficacy of lifestyle intervention and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity. Design, Setting, and Patients A randomized controlled trial (October 2004-December 2006) involving 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya Hospital, Central South University, China. Participants who gained more than 10% of their predrug weight were assigned to 1 of 4 treatment groups. Interventions Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of metformin alone, 750 mg/d of metformin and lifestyle intervention, or lifestyle intervention only. Main Outcome Measures Body mass index, waist circumference, insulin levels, and insulin resistance index. Results All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval [CI], 1.3-2.3), insulin resistance index of 3.6 (95% CI, 2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm). The metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95% CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95 CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2 cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight, BMI, and waist circumference reduction. Conclusions Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic-induced weight gain. Lifestyle intervention plus metformin showed the best effect on weight loss. Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone. Trial Registration clinicaltrials.gov Identifier: NCT00451399