Weight-independent effects of Roux-en-Y gastric bypass surgery on remission of nonalcoholic fatty liver disease in mice.

OBJECTIVE:Obesity is a driver of non-alcoholic fatty liver disease (NAFLD), and interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR), may serve as effective therapies. This study compared the effects of Roux-en-Y gastric bypass surgery (RYGB) and CR on hepatic function in mice with obesity and NAFLD. METHODS:C57BL/6J mice were fed a high-fat diet to promote obesity. At 16 weeks of age, mice were randomized to sham surgery (sham), RYGB, or CR weight matched to RYGB (WM). Body weight/composition, food intake, and energy expenditure (EE) were measured throughout treatment. Liver histopathology was evaluated from H&E-stained sections. Hepatic enzymes and glycogen content were determined by ELISA. Transcriptional signatures were revealed via RNA sequencing. RESULTS:RYGB reduced hepatic lipid content and adiposity while increasing EE and lean body mass relative to WM. Hepatic glycogen and bile acid content were increased after RYGB relative to sham and WM. RYGB activated enterohepatic signaling and genes regulating hepatic lipid homeostasis. CONCLUSIONS:RYGB improved whole-body composition and hepatic lipid homeostasis to a greater extent than CR in mice. RYGB was associated with discrete remodeling of the hepatic transcriptome, suggesting that surgery may be mechanistically additive to CR.