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. Keyterms GLP-1R, Y1R, Y2R, anti-obesity drugs, multiagonistic peptides, insulin secretion