A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients. ### Competing Interest Statement This work was supported by the United States Department of Defense through a Congressionally Directed Medical Research Program Award (W81XWH1010299) to R.P.D. and C.L.R. and funding from the National Institutes of Health (R01 DK17047, the DRC Cell Function Analysis Core) and the National Science Foundation (STTR 1853066) to I.R.S. G.G.H. received funding via subcontract under National Institutes of Health (R01 DK128443) to R.P.D., M.R.H. and Bart C. De Jonghe. Biochemical analyses were performed at the University of Washington Nutrition and Obesity Research Center (UW NORC) which is supported by grant P30 DK035816 from the National Institute of Diabetes and Digestive and Kidney Diseases. R.P.D. acknowledges the SOURCE program at Syracuse University for funding provided for A.M.G. R.P.D. is a Scientific Advisory Board member of Balchem Corporation, New Hampton, NY, and Xeragenx LLC. (St. Louis, MO); these organizations played no role in the design, execution, or analysis of the results of these studies. R.P.D. and B.T.M. are named authors of a patent pursuant to this work that is owned by Syracuse University. I.R.S. has financial ties to EnTox Sciences, Inc. (Mercer Island, WA), the manufacturer/distributor of the BaroFuse perifusion system used in this study. M.R.H. receives funding from Zealand Pharma, Novo Nordisk, Eli Lilly & Co., and Boehringer Ingelheim; these funds were not used to support these studies. M.R.H. and R.P.D. are co-founders and co-owners of Cantius Therapeutics (Lansdale, PA), which also played no role in these studies.