Adipose reduction in the activity of the repressor ICER is responsible for insulin resistance elicited by the transcriptional factors CREB in obesity

BACKGROUND AND AIMS: Sustained adipose activation of the transcriptional activators cAMP response binding proteins (CREB) in obesity leads to impaired expression of the glucose transporter GLUT4 and adiponectin (adipoq) in mice model of obesity. Diminution of GLUT4 and adipoq caused by CREB is indirect and relies on the increased repressive activity of the CREB target gene activating transcription factor 3 (ATF3). Specific inactivation of CREB in adipocytes decreases ATF3 production and improves whole-body insulin sensitivity of mice in the context of diet-induced obesity. Thus, elevation of CREB activity is a key mechanism responsible for adipocyte dysfunction and systemic insulin resistance. The inducible cAMP early repressor (ICER) is a negative regulator of the CREB activity. In fact, ICER antagonizes the CREB factor by competing for the regulation of similar target genes. The goal of the study was to investigate whether loss of ICER expression in adipocytes could be responsible for increased CREB activity in obesity. MATERIALS AND METHODS: Mice C57bl6 were fed with a high fat diet (HFD) for 12 weeks to increase body weight and generate insulin resistance. Biopsies of visceral adipose tissues (VAT) were prepared from human lean (BMI=24}0.5 Kg/m2) or obese subjects (BMI>35 Kg/m2). Total RNA and protein were prepared from white adipose tissues (WAT) of chow- or HFD-fed mice and VAT of lean and obese subjects. Activities of CREBs and ICER were monitored by electromobility shift assays (EMSA). The role of ICER on CREB activity was confirmed in 3T3-L1 adipocytes cells. Briefly after differentiation, the cells were electroporated with the plasmid coding for ICER cDNA. Gene expression was quantified by quantitative real-time PCR and western Blotting experiments. RESULTS: The expression of ICER is reduced in WAT of HFD-induced obese mice when compared to chow mice as measured by real-time PCR and EMSA. Similar result was found in human tissues. Reduction in ICER expression was associated with increased ATF3 expression and decreased adipoq and GLUT4 contents. Diminution in ICER levels was observed in adipocytes fraction whereas its expression was unchanged in stroma vascular fraction of WAT. Overexpression of ICER in 3T3-L1 adipocytes silenced the expression of ATF3, confirming the regulation of the factor by ICER. The expression of ICER is regulated by histone deacetylases activity (HDAC). Inhibition of HDACs in 3T3-L1 adipocytes cells using trichostatin inhibited the production of ICER. The whole activity of HDAC was reduced in WAT and VAT of obese mice and human obese subjects. CONCLUSION: Impaired adipose expression of ICER is responsible of increased CREB activity in adipocytes in obesity. This mechanism relies on reduction of the HDAC activity.

Differing trends in the association between obesity and self-reported health in Portugal and Switzerland: data from national health surveys 1992-2007.

BACKGROUND: The escalating prevalence of obesity might prompt obese subjects to consider themselves as normal, as this condition is gradually becoming as frequent as normal weight. In this study, we aimed to assess the trends in the associations between obesity and self-rated health in two countries. METHODS: Data from the Portuguese (years 1995-6, 1998-6 and 2005-6) and Swiss (1992-3, 1997, 2002 and 2007) National Health Surveys were used, corresponding to more than 130,000 adults (64,793 for Portugal and 65,829 for Switzerland). Body mass index and self-rated health were derived from self-reported data. RESULTS: Obesity levels were higher in Portugal (17.5% in 2005-6 vs. 8.9% in 2007 in Switzerland, p < 0.001) and increased in both countries. The prevalence of participants rating their health as "bad" or "very bad" was higher in Portugal than in Switzerland (21.8% in 2005-6 vs 3.9% in 2007, p < 0.001). In both countries, obese participants rated more frequently their health as "bad" or "very bad" than participants with regular weight. In Switzerland, the prevalence of "bad" or "very bad" rates among obese participants, increased from 6.5% in 1992-3 to 9.8% in 2007, while in Portugal it decreased from 41.3% to 32.3%. After multivariate adjustment, the odds ratio (OR) of stating one self's health as "bad" or "very bad" among obese relative to normal weight participants, almost doubled in Switzerland: from 1.38 (95% confidence interval, CI: 1.01-1.87) in 1992-3 to 2.64 (95% CI: 2.14-3.26) in 2007, and similar findings were obtained after sample weighting. Conversely, no such trend was found in Portugal: 1.35 (95% CI: 1.23-1.48) in 1995-6 and 1.52 (95% CI: 1.37-1.70) in 2005-6. CONCLUSION: Obesity is increasing in Switzerland and Portugal. Obesity is increasingly associated with poorer self-health ratings in Switzerland but not in Portugal.

Laparoscopic Gastric Banding Outcomes Do Not Depend on Device or Technique. Long-Term Results of a Prospective Randomized Study Comparing the Lapband® and the SAGB®.

BACKGROUND: Gastric banding still represents one of the most widely used bariatric procedures. It provides acceptable weight loss in many patients, but has frequent long-term complications. Because different types of bands may lead to different results, we designed a randomized study to compare the Lapband® with the SAGB®. We hereby report on the long-term results. METHODS: Between December 1998 and June 2002, 180 morbidly obese patients were randomized between Lapband® or SAGB®. Weight loss, long-term morbidity, and need for reoperation were evaluated. RESULTS: Long-term weight loss did not differ between the two bands. Patients who maintained their band had an acceptable long-term weight loss of between 50 and 60 % EBMIL. In both groups, about half the patients developed long-term complications, with about 50 % requiring major redo surgery. There was no difference in the overall rates of long-term complications or failures between the two groups, but patients who had a Lapband® were significantly more prone to develop band slippage/pouch dilatation (13.3 versus 0 %, p < 0,001). CONCLUSIONS: Although in the absence of complication, gastric banding leads to acceptable weight loss; the long-term complication and major reoperation rates are very high independently from the type of band used or on the operative technique. Gastric banding leads to relatively poor overall long-term results and therefore should not be considered the procedure of choice for the treatment of morbid obesity. Patients should be informed of the limited overall weight loss and the very high complication rates.

Discordances in the application of different criteria for quantification of paediatric abdominal obesity: an analysis of two Swiss studies.

Several definitions of paediatric abdominal obesity have been proposed but it is unclear whether they lead to similar results. We assessed the prevalence of abdominal obesity using five different waist circumference-based definitions and their agreement with total body fat (TBF) and abdominal fat (AF). Data from 190 girls and 162 boys (Ballabeina), and from 134 girls and 113 boys (Kinder-Sportstudie, KISS) aged 5-11 years were used. TBF was assessed by bioimpedance (Ballabeina) or dual energy X-ray absorption (KISS). On the basis of the definition used, the prevalence of abdominal obesity varied between 3.1 and 49.4% in boys, and 4.7 and 55.5% in girls (Ballabeina), and between 1.8 and 36.3% in boys and 4.5 and 37.3% in girls (KISS). Among children considered as abdominally obese by at least one definition, 32.0 (Ballabeina) and 44.7% (KISS) were considered as such by at least two (out of five possible) definitions. Using excess TBF or AF as reference, the areas under the receiver operating curve varied between 0.577 and 0.762 (Ballabeina), and 0.583 and 0.818 (KISS). We conclude that current definitions of abdominal obesity in children lead to wide prevalence estimates and should not be used until a standard definition can be proposed.

New strategies in the modulation of fatty acid oxidation as a treatment for obesity

Strategies that enhance fat degradation or reduce caloricfood intake could be considered therapeutic interventions to reduce notonly obesity, but also its associated disorders. The enzyme carnitinepalmitoyltransferase 1 (CPT1) is the critical rate-determining regulatorof fatty acid oxidation (FAO) and might play a key role in increasingenergy expenditure and controlling food intake. Our group has shownthat mice overexpressing CPT1 in liver are protected from weight gain,the development of obesity and insulin resistance. Regarding foodintake control, we observed that the pharmacological inhibition ofCPT1 in rat hypothalamus decreased food intake and body weight.This suggests that modulation of CPT1 activity and the oxidation offatty acids in various tissues can be crucial for the potential treatmentof obesity and associated pathologies.

Prevalence and determinants of obesity in children in public schools of Sintra, Portugal

OBJECTIVE: To assess the prevalence of and the factors related to overweight and obesity in a sample of children from the region of Sintra, Portugal. METHODS AND PROCEDURES: Cross-sectional study, stratified for freguesia with random selection of schools. Height, weight, triceps skinfold, upper arm and waist circumferences were measured, and overweight/obesity defined according to international criteria. Breast-feeding, number of daily meals and parents' height and weight data were also collected. RESULTS: One thousand two hundred and twenty-five children aged 6-10 years were assessed. Overall prevalence of overweight and obesity was 35.6% (23% overweight and 12.6% obesity). Overweight or obese children had higher triceps skinfold, upper arm circumference, arm muscle area, and waist circumference than their normal weight counterparts (P < 0.001). On multivariate analysis, relatively to a child without obese progenitors, a child with one obese progenitor had an obesity risk multiplied by 2.78 (95% confidence interval (CI): 1.76-4.38), while a child with two obese progenitors had a risk multiplied by 6.47 (95% CI: 5.59-16.19). Conversely, being picky was significantly related with a smaller risk of obesity: for boys, odds ratio (OR) = 0.15 (95% CI: 0.04-0.63); for girls, OR = 0.19 (95% CI: 0.06-0.64). Finally, no relationships were found between obesity, birth weight, birth height or breast-feeding. DISCUSSION: Prevalence of overweight and obesity are elevated among children of the Sintra region in Portugal compared to most other regions of Europe. The relationship with the parents' nutritional state stresses the need to target families for preventing obesity.

Absence of association between specific common variants of the obesity-related FTO gene and psychological and behavioral eating disorder phenotypes.

Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single-nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1,085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls. © 2011 Wiley-Liss, Inc.

Decreased glucose-induced thermogenesis after weight loss in obese subjects: a predisposing factor for relapse of obesity?

Glucose-induced thermogenesis (GIT) after a 100-g oral glucose load was measured by continuous indirect calorimetry in 32 nondiabetic and diabetic obese subjects and compared to 17 young and 13 middle aged control subjects. The obese subjects were divided into three groups: A (n = 12) normal glucose tolerance, B (n = 13) impaired glucose tolerance, and C (n = 7) diabetics, and were studied before and after a body weight loss ranging from 9.6 to 33.5 kg consecutive to a 4 to 6 months hypocaloric diet. GIT, measured over 3 h and expressed as percentage of the energy content of the load, was significantly reduced in obese groups A and C (6.2 +/- 0.6, and 3.8 +/- 0.7%, respectively) when compared to their age-matched control groups: 8.6 +/- 0.7 (young) and 5.8 +/- 0.3% (middle aged). Obese group B had a GIT of 6.1 +/- 0.6% which was lower than that of the young control group but not different from the middle-aged control group. After weight loss, GIT in the obese was further reduced in groups A and B than before weight loss: ie, 3.4 +/- 0.6 (p less than 0.001), 3.7 +/- 0.5 (p less than 0.01) respectively, whereas in group C, weight loss induced no further diminution in GIT (3.8 +/- 0.6%). These results support the concept of a thermogenic defect after glucose ingestion in obese individuals which is not the consequence of their excess body weight but may be one of the factors favoring the relapse of obesity after weight loss.

The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression.

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21 932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.

Improved Surgical Technique Reduces Complications at the Gastro-jejunostomy After Laparoscopic Roux-en-Y Gastric Bypass

Introduction: Roux-en-Y gastric bypass (RYGBP) is one of the commonest procedure for morbid obesity. It is associated with effective long-term weight loss, but can lead to significant complications, especially at the gastrojejunostomy (GJS) Patients and Methods: All the patients undergoing laparoscopic RYGBP at one of our two institutions were included in this study, in which we compared two different techniques for the construction of the GJS and their effects on the incidence of complications. In group A, anatomosis was performed on the posterior aspect of the gastric pouch. In group B it was performed across the staple line used to form the gastric pouch. A 21-mm circular stapler was used in all patients. Results: A total of 1128 patients were included between June 1999 and September 2009, 639 in group A and 488 in group B. Sixty patients developed a total of 65 complications at the GJS, with 14 (1,2 %) leaks, 42 (3,7 %) stricture, and 9 (0,8 %) marginal ulcers. Leaks (0,2 versus 2 %, p=0,005) and strictures (0,8 versus 5,9%, p<0,0001) were significantly fewer in group B than in group A. Conclusions: Improved surgical technique, with the GJS across the staple line used to form the gastric pouch, significantly reduces the rate of anastomotic complications at the GJS. A circular 21-mm stapler can be used with a low complication rate, and especially a low stricture rate. Additional methods to limit complications at the GJS are probably not routinely warranted.

The effect of obesity, age, puberty and gender on resting metabolic rate in children and adolescents.

During puberty fat-free mass (FFM) and fat mass (FM) change quickly and these changes are influenced by sex and obesity. Since it is not completely known how these changes affect resting metabolic rate (RMR), the aim of the present study was to investigate the effect of body composition, age, sex and pubertal development of postabsorptive RMR in 9.5- to 16.5- year-old obese and non-obese children. Postabsorptive RMR was measured in a sample of 371 pre- and postpubertal children comprising 193 males (116 non-obese and 77 obese) and 178 females (119 non-obese and 59 obese). RMR was assessed by indirect calorimetry using a ventilated hood system for 45 min after an overnight fast. Body composition (FFM and FM) was estimated from skinfold measurements. The mean (+/- SD) RMR was significantly (P < 0.001) lower in non-obese (males: 5600 +/- 972 kJ/24 h; females: 5112 +/- 632 kJ/24 h) than in obese (males: 7223 +/- 1220 kJ/24 h; females: 6665 +/- 1106 kJ/24 h) children. This difference became non-significant when RMR was adjusted for body composition (FFM+FM). However, the difference between the genders still remained significant (control male: 6118 +/- 507, control female: 5652 +/- 507, P < 0.001; obese male: 6256 +/- 507, obese female: 5818 +/- 507 kJ/24 h, P < 0.001). The main determinant of RMR was FFM. In the whole cohort. FFM explained 79.8% of the variation in RMR, followed by age, gender and FM adding further 3.8%, 1.1% and 0.8% to the predictability of RMR, respectively. No significant contribution for study group (obese, non-obese), pubertal stage, or fat distribution was found in the regression for RMR. The adjusted value of RMR (for FFM and FM) slightly, but significantly (P < 0.01) decreased between the age of 10-16 years, demonstrating the important effect of age on RMR. CONCLUSIONS: The resting metabolic rate of obese and control children is not different when adjusted for body composition. The main determinant of RMR is the fat-free mass, however, age, gender and fat mass are also significant factors. Pubertal development and fat distribution do not influence RMR independently from the changes in body composition.

Association between Inflammatory and Obesity Markers in a Swiss Population-Based Sample (CoLaus Study).

Objective: To assess the associations between obesity markers (BMI, waist circumference and %body fat) and inflammatory markers (interleukin-1β (IL-1β); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein (hs-CRP)). Methods: Population sample of 2,884 men and 3,201 women aged 35-75 years. Associations were assessed using ridge regression adjusting for age, leisure-time physical activity, and smoking. Results: No differences were found in IL-1β levels between participants with increased obesity markers and healthy counterparts; multivariate regression showed %body fat to be negatively associated with IL-1β. Participants with high %body fat or abdominal obesity had higher IL-6 levels, but no independent association between IL-6 levels and obesity markers was found on multivariate regression. Participants with abdominal obesity had higher TNF-α levels, and positive associations were found between TNF-α levels and waist circumference in men and between TNF-α levels and BMI in women. Obese participants had higher hs-CRP levels, and these differences persisted after multivariate adjustment; similarly, positive associations were found between hs-CRP levels and all obesity markers studied. Conclusion: Obesity markers are differentially associated with cytokine levels. %Body fat is negatively associated with IL-1β; BMI (in women) and waist circumference (in men) are associated with TNF-α; all obesity markers are positively associated with hs-CRP. Copyright © 2012 S. Karger GmbH, Freiburg.