1 The PYY / Y 2 R-deficient mouse responds normally to 2 high-fat diet and gastric bypass surgery 3

Background/Goals: The gut hormone PYY secreted from intestinal L-cells has been 15 implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery 16 and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and 17 body weight. Methods: Here we assessed the role of Y2R signaling in the response to lowand high18 fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body 19 composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient 20 (Y2RKO) and wildtype mice made obese on high-fat diet. Results: Both male and female Y2RKO 21 mice responded normally to lowand high-fat diet in terms of body weight, body composition, 22 fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of 23 age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to 24 WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and 25 significant improvements in fasting insulin, glucose tolerance, HOMA-IR, and liver weight 26 compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to 27 RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were 28 similar to WT mice. Conclusions: PYY signaling through Y2R is not required for the normal appetite29 suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. 30 Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut 31 satiety hormones such as GLP-1 remain to be investigated. 32