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Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice

Alessandro Pocai1, Paul E Carrington, Jennifer R Adams

  • 1Merck Research Laboratories, Rahway, NJ, USA.

Diabetes
|July 16, 2009
PubMed
Abstract

Insights

Dual GLP-1/glucagon receptor agonism effectively reverses obesity in mice. This dual-action peptide offers a promising new therapeutic strategy for treating obesity by enhancing weight loss and improving metabolic health.

Area of Science:

  • Metabolic research
  • Pharmacology
  • Obesity research

Background:

  • Oxyntomodulin (OXM) is a dual glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) agonist known to reduce body weight.
  • The metabolic benefits of OXM are primarily attributed to GLP1R agonism.
  • Distinct metabolic effects of dual GLP1R/GCGR agonists compared to GLP1R-selective agonists require investigation.

Purpose of the Study:

  • To compare the metabolic effects of a novel dual GLP1R/GCGR agonist (DualAG) with a GLP1R-selective agonist (GLPAG) in diet-induced obese (DIO) mice.
  • To determine if dual agonism offers distinct metabolic advantages over selective GLP1R agonism.
  • To elucidate the specific roles of GLP1R and GCGR activation in the pharmacological actions of the dual agonist.

Main Methods:

  • Development of protease-resistant DualAG and GLPAG peptides matched for GLP1R potency and pharmacokinetics.
  • Chronic dosing studies in DIO mice to compare weight loss, caloric intake, glucose control, and lipid profiles.
  • Acute studies and studies in knockout mice (Glp1r(-/-) and Gcgr(-/-)) to differentiate receptor contributions.

Main Results:

  • DualAG demonstrated superior weight loss, lipid-lowering, and antihyperglycemic effects compared to GLPAG.
  • Chronic DualAG treatment led to more significant improvements in insulin, leptin, and adiponectin levels.
  • Dual agonism increased fatty acid oxidation, reduced hepatic steatosis, and its anti-obesity effects necessitated activation of both GLP1R and GCGR.

Conclusions:

  • Sustained GLP1R/GCGR dual agonism effectively reverses obesity in DIO mice.
  • This dual-acting peptide represents a novel therapeutic approach for obesity treatment.
  • Dual receptor activation is crucial for the observed anti-obesity and metabolic benefits.

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