237-LB: Weight-Independent Effects of Roux-en-Y Gastric Bypass Surgery on Remission of Nonalcoholic Fatty Liver Disease in Mice

Abstract

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD. Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA. Results: RYGB & WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P<0.001) . Decreased body weight was attributable to lower food intake in WM compared to RYGB and Sham (P<0.0001) . WM decreased EE relative to RYGB and Sham (WM:8.6±0.4 vs. RYGB:10.4±0.4 vs. Sham:10.5±0.6 kcals/day, P<0.001) . RYGB decreased hepatic lipid content to a greater extent than WM (92.6 vs. 76.5 % reduction, P=0.02) . RYGB and WM similarly decreased AST and ALT activity relative to Sham. RYGB increased hepatic glycogen relative to both Sham and WM (P<0.001) . Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB. Disclosure C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None. Funding National Institutes of Health (U54GM104940)