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

Abstract

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.

Keywords: Body weight; Calorie intake; Drug intervention; Glucose tolerance; Monomeric multi-receptor agonist; Obesity.

Fig. 1.

Sequences of Ex-4, PYY_3-36, and monomeric triple agonist peptide GEP44. Lowercase and underlined letters denote d-amino acids.

Fig. 2.

A: In silico modeling using Molecular Operating Environment (MOE) analysis of the C-terminal portion of GEP44 (pink) and PYY_3-36 (green) at the Y2R. Scores for GEP44 and PYY_3-36 were −21.02 and −19.82, respectively. FIG. 2B: Diagram summarizing the important interactions between GEP44 and PYY_3-36 with Y2R as predicted with MOE.

Fig. 3.

Changes in body weight and food intake over 28-d treatment with GEP44 vs. LIRA vs. vehicle and vehicle pair-fed to GEP44 or LIRA in DIO male (A–D) and female (E–H) Wistar rats. Rats in different groups were matched based on baseline food intake and body weight gain trajectory. A group of age-matched lean females were included as controls (E, F). Changes of body weight were followed in response to GEP44 and LIRA at doses escalating from 5 to 50 nmol/kg, or pair-feeding to the same amount food consumed by their GEP44 treated animals. In both sexes, reductions of body weight and food intake in response to GEP44 vs. LIRA were greater during the experiment (A, B, E, F), and from baseline to the end of the treatment (C, G). In addition, significant reductions of HOMA-IR were seen in male rats in response to GEP44, LIRA, pair-feeding to GEP44 or LIRA (D), but those differences were not significant in female rats (H). Data for pair-fed animals are mostly not visible due to superimposition of drug-treated animal data (B, E, F).

Fig. 4.

Changes in post-dextrose bolus blood glucose during a 120 min intraperitoneal glucose tolerance test before and after 14-d treatment with GEP44 (A) vs. pair-fed to GEP-44 (B) vs. LIRA (D) vs. vehicle (E) in DIO female Wistar rats. Animals were matched based on baseline food intake and body weight gain trajectory. Significant reductions of blood glucose were noted in response to treatment with GEP44 and LIRA as well as pair feeding to GEP44 (A, B, D, F). During the glucose tolerance test, insulin was assessed at −30, 0, 15, 30, and 60 min in relation to glucose ip bolus. Insulin secretion was significantly stimulated in response to GEP44 and LIRA (C).