Development of Anorexigenic and Glucoregulatory Chimeric Peptides

PROJECT SUMMARY Current pharmacological obesity treatments have limited long-term efficacy with little or no impact on disease reversal. The proposed research focuses on the fact that the pathophysiology of obesity is driven by dysregulation of multiple, but inter-related pathways. As such, we hypothesize that successful treatments for obesity will require a new generation of therapeutics that target multiple receptors of complementary neurocircuits regulating the controls of energy balance. While considerable interest has focused on glucagon-like peptide 1 receptor agonists alone, recent evidence also shows that Y1-R agonism facilitates trans- differentiation of pancreatic α-cells to β-cells, thus increasing insulin secretion and reducing glucagon secretion, while peripheral administration of the neuropeptide Y2-receptor (Y2-R) agonist PYY3-36 has been shown to reduce caloric intake. We recently developed the first tri-agonist of GLP-1R, Y1-R and Y2-R (GEP44), obtained after extensive studies in lean and DIO rodent (mice and rats) and mammalian (musk shrew) studies of food intake, weight loss, glucose uptake, nausea, and emesis. GEP44 shows potent anorectic effects in lean and diet-induced obese rats and mice in acute and chronic studies with up to 80 % reduction of food intake and stronger reductions of body weight than known GLP-1RAs, including liraglutide, and without visceral malaise (common to GLP-1RAs alone). We have shown GEP44 can penetrate the brainstem and bind to GLP-1R, and Y-family receptors in the area postrema and nucleus tractus solitarius, and facilitate glucose entry into muscle via the Y1-R. Our success with this innovative triple agonism led us to further development and refinements of monomeric peptides, including the development of a long-acting form, which we plan to test in vivo with this project. To further test the simultaneous agonism of these three receptors, critical in glucoregulation, food intake, and energy balance, we propose complimentary studies by a multi-PI team of established investigators with extensive collaborative experience to investigate the following aims: Aim 1 will elucidate tissue-specific synergism of tri- vs. single- receptor agonism and targets underlying the efficacy of GEP44 focusing on brain areas of energy homeostasis. Included therein is an unbiased cell transcriptomics study to test the effects, on brainstem circuitry, of GEP44 in diet-induced obese (DIO) rats. Furthermore, characteristics of different lipidated long-acting analogs at two primary positions focusing on receptor agonism and binding, internalization, β-arrestin recruitment, albumin binding, and proteolysis protection will be established in vitro. Aim 2 will focus on pharmacokinetics and on testing long-acting GEP44 vs. GEP44 on energy expenditure, body weight change, food intake, gastric emptying, and potential adverse effects to determine acute and chronic effects in rats. Aim 3 will establish the effects of long-acting GEP44 on post meal glucose levels, incretin independent insulin secretion, insulin sensitivity, and on glucose uptake in diabetic obese rats. Such studies will lead to significantly improved, clinically beneficial novel therapeutics for the treatment of obesity and associated metabolic disorders.