Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist

Introduction: While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. Objective: As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. Methods: Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. Results: Upon conclusion at 28-d, body weight reduction compared to vehicle was −15.6%/-11.9% in response to GEP44, vs. −9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (−30%; p < 0.0001), vs. LIRA (−10%), and in male rats GEP44 (−39%; p < 0.0001), vs. LIRA (−20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. Conclusion: The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.