%0 Journal Article
%T Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist.
%A Elfers CT
%A Chichura KS
%A Ashlaw EF
%A Chepurny OG
%A Holz GG
%A Doyle RP
%A Roth CL
%J Clin Nutr
%V 43
%N 7
%D 2024 Jul 28
%M 38861891
%F 7.643
%R 10.1016/j.clnu.2024.05.035
%X <B>BACKGROUND: </B>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.<BR><B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.