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

Abstract

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.

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

“…We also extend previous findings from our laboratory [12; 13] to demonstrate that GEP44 reduces core temperature (surrogate measure of energy expenditure) in both male and female mice, similar to what we described earlier herein following exendin-4 treatment. These data are also consistent with a previous report by Hayes and colleagues showing that the GLP-1R agonist, exendin-4, produced a long-lasting reduction of core temperature (hypothermia) that lasted for 4 hours following systemic (intraperitoneal (IP)) injections in rats [24].…”

“…We extend previous findings from our laboratory [12; 13] and demonstrate that the effects of GEP44 to elicit weight loss in both male and female mice are primarily driven by GLP-1R. These effects are mediated, at least in part, by reductions of energy intake.…”

“…GEP44 was synthesized in the Doyle lab as previously described [12]. Fresh solutions of GEP44 and exendin-4 (ENZO; Farmingdale, NY) were prepared, frozen and thawed prior to the onset of each experiment ( Study 1 ).…”

“…We recently designed the novel chimeric peptide, GEP44, which binds to GLP-1R, Y1R and Y2R [12]. We found that systemic administration of GEP44 reduced energy intake and BW in both lean [13] and diet-induced obese rats [12; 13].…”

“…We recently designed the novel chimeric peptide, GEP44, which binds to GLP-1R, Y1R and Y2R [12]. We found that systemic administration of GEP44 reduced energy intake and BW in both lean [13] and diet-induced obese rats [12; 13]. Importantly, GEP44 also reduced energy intake at doses that were not associated with significant pica behavior (kaolin intake) in rats [13] or emesis in musk shrews [13].…”