Combined loss of GLP-1R and Y2R does not alter progression of high-fat diet-induced obesity or response to RYGB surgery in mice

Brandon B. Boland, Michael B. Mumphrey, Zheng Hao, R. Leigh Townsend, Benji Gill, Stephanie Oldham, Sarah Will, Christopher D. Morrison, Sangho Yu, Heike Münzberg, Christopher J. Rhodes, James L. Trevaskis, Hans-Rudolf Berthoud

Roux-en-Y gastric bypass (RYGB) results in large and sustained weight loss. It is thought that the beneficial effects of RYGB are mediated, at least in part, by the gut hormones GLP-1 and PYY. Boland, Mumphrey, et al. hypothesized that deleting both signaling pathways simultaneously in GLP1R/Y2R double knockout mice would significantly attenuate the effects of RYGB. Unexpectedly, however, combined loss of GLP-1R and Y2R signaling had only minor effects on body weight, fat mass, and glucose homeostasis. Furthermore, RYGB was just as effective in lowering body weight and adiposity as well as improving glucose tolerance and insulin sensitivity.

Objective: Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine–tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery.

Methods: The metabolic effects of high-fat diet and the ability of Roux-en-Y gastric bypass surgery to lower food intake and body weight, as well as improve glucose handling, was tested in GLP1R and Y2R-double knockout (GLP1RKO/Y2RKO) and C57BL6J wildtype (WT) mice.

Results: GLP1RKO/Y2RKO and WT mice responded similarly for up to 20 weeks on high-fat diet and 16 weeks after RYGB. There were no significant differences in loss of body and liver weight, fat mass, reduced food intake, relative increase in energy expenditure, improved fasting insulin, glucose tolerance, and insulin tolerance between WT and GLP1RKO/Y2RKO mice after RYGB.

Conclusions: Combined loss of GLP1R and Y2R-signaling was not able to negate or attenuate the beneficial effects of RYGB on body weight and glucose homeostasis in mice, suggesting that a larger number of signaling pathways is involved or that the critical pathway has not yet been identified.