Publications (79) View all
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Article: Weight loss after gastric bypass is associated with a variant at 15q26.1.
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ABSTRACT: The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB.The American Journal of Human Genetics 05/2013; 92(5):827-34. · 10.60 Impact Factor -
Dataset: JCEM 2012 manuscript
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Article: Inverse Regulation of Inflammation and Mitochondrial Function in Adipose Tissue Defines Extreme Insulin Sensitivity in Morbidly Obese Patients.
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ABSTRACT: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin-resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ∼320 nondiabetic (HbA(1c) <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment-insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.Diabetes 12/2012; · 8.29 Impact Factor -
Article: Advantages of percent weight loss as a method of reporting weight loss after Roux-en-Y gastric bypass.
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ABSTRACT: OBJECTIVE: Although Roux-en-Y gastric bypass (RYGB) is an effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (ΔBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively, it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB-induced WL. DESIGN AND METHODS: To determine the WL measure least associated with pBMI, outcomes of 846 patients undergoing RYGB were analyzed. RESULTS: Patients in this cohort had an average pBMI of 50.0 kg/m(2) at baseline. At weight nadir, they lost an average 19.4 kg/m(2) , 38.7% WL, and 81.2% EBWL. pBMI was strongly and positively associated with ΔBMI at both 1 year (r = 0.56, P = 4.7 × 10(-51) ) and nadir (r = 0.58, P = 2.8 × 10(-77) ) and strongly but negatively associated with %EBWL at 1 year (r = -0.52, P = 3.8 × 10(-44) ) and nadir (r = -0.45, P = 7.2×10(-43) ). In contrast, pBMI was not significantly associated with %WL at 1 year (r = 0.04, P = 0.33) and only weakly associated at nadir (r = 0.13, P = 0.0002). CONCLUSIONS: Of the metrics examined, %WL is the parameter describing WL after RYGB least influenced by pBMI. It thus improves comparison of WL outcomes across studies of patients undergoing surgery and facilitates the most sensitive identification of novel predictors of surgery-induced WL. We therefore is recommend that %WL be adopted more broadly in reporting weight loss after RYGB.Obesity 11/2012; · 4.28 Impact Factor -
Article: Isolated Duodenal Exclusion Increases Energy Expenditure and Improves Glucose Homeostasis in Diet-induced Obese Rats.
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ABSTRACT: Roux-en-Y gastric bypass (RYGB) in rodent models reduces food intake (FI), increases resting energy expenditure (EE) and improves glycemic control. We have shown that mimicking the duodenal component of RYGB by implantation of a 10cm endoluminal sleeve device (ELS-10) induces weight loss and improves glycemic control in diet-induced obese (DIO) rats. We sought to determine the mechanisms and structural requirements of these effects. We examined the effects of ELS-10 devices implanted in male DIO rats on body weight, FI, meal patterns, total and resting EE, and multiple parameters of glucose homeostasis, comparing them to sham-operated (SO) rats and to SO rats weight-matched to the ELS-10-treated group. To determine the extent of duodenal exclusion required to influence metabolic outcomes, we compared the effects of implanting 10, 4 or 1cm ELS devices. ELS-10 rats exhibited 13% higher total and 9% higher resting EE than SO controls. ELS-10 rats also exhibited enhanced postprandial GLP-1 secretion and improved glucose tolerance and insulin sensitivity out of proportion to the effects of weight loss alone. Implantation of 4 or 1cm ELS devices had no effect on EE and limited effects on glucose homeostasis. Complete duodenal exclusion with ELS-10 induces weight loss by decreasing FI and increasing EE, and improves glycemic control through weight loss-independent mechanisms. Thus, signals originating in the proximal small intestine appear to exert a direct influence on the physiological regulation of EE and glucose homeostasis. Their selective manipulation could provide effective new therapies for obesity and diabetes that mimic the benefits of RYGB.AJP Regulatory Integrative and Comparative Physiology 09/2012; · 3.34 Impact Factor
