SummaryOverweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3–6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P<1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P<0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P<9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.

Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.

BackgroundPrevious studies show that ‘poor responders’ to Roux-en-Y gastric bypass (RYGBP) may be identified on the basis of early postoperative weight loss. Early identification of poor responders could allow earlier provision of postoperative behavioural and/or intensive lifestyle interventions and enhance their maximal weight loss. Our aim was to investigate whether early postoperative weight loss predicts the maximal weight loss response after RYGBP and sleeve gastrectomy (SG).MethodsWe undertook a retrospective cross-sectional study of 1,456 adults who underwent either RYGBP (n = 918) or SG (n = 538) as a primary procedure in one of two European centres. Postoperative weight loss was expressed as weight loss velocity (WLV) and percentage weight loss. Linear regression analyses were performed to determine the association of early postoperative weight loss with maximal %WL, including adjustment for baseline variables.ResultsThere was marked variability in maximal %WL following both RYGBP (mean 32.9 %, range 4.1–60.9 %) and SG (mean 26.2 %, range 1.1–58.3 %). WLV 3–6 months postoperatively was more strongly associated with maximal %WL (r2 = 0.32 for RYGBP and r2 = 0.26 for SG, P < 0.001 for both) than either WLV 0–6 weeks or 6 weeks to 3 months postoperatively (r2 = 0.14 and 0.10 for RYGBP, respectively; r2 = 0.18 and 0.21 for SG, respectively; P < 0.001 for all). Multiple linear regression analysis, including baseline variables of age, sex, preoperative BMI, type 2 diabetes, ethnicity, and bariatric centre, revealed that 3–6 month WLV was an independent predictor of maximal %WL in both SG and RYGBP groups (standardised β-coefficients 0.51 and 0.52, respectively; P < 0.001 for both).ConclusionsThere is a marked variability in weight loss response following RYGBP and SG. Early postoperative weight loss can be used to identify patients whose predicted weight loss trajectories are suboptimal. Early targeting of poor responders with more intensive postoperative lifestyle and behavioural support could potentially enhance their weight loss response.