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

Jun 11, 2024Clinical nutrition (Edinburgh, Scotland)

Lower food intake and weight loss in obese rats after long-term treatment with a single-peptide drug targeting multiple systems

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Abstract

Body weight reduction after 28 days was 15.6% in male rats and 11.9% in female rats treated with GEP44.

GEP44 treatment resulted in significant reductions in cumulative food intake, with female rats showing a decrease of -30% compared to LIRA's -10%.
Male rats treated with GEP44 experienced a food intake reduction of -39%, while LIRA resulted in a -20% reduction.
Both GEP44 and LIRA stimulated glucose-induced insulin secretion similarly in glucose tolerance tests.
The findings suggest that targeting multiple receptors may lead to more effective long-term weight loss and energy balance regulation.

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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.

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

Abstract

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