Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice

Abstract

OBJECTIVEOxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.RESEARCH DESIGN AND METHODSWe developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r−/− and Gcgr−/− mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.RESULTSPeptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.CONCLUSIONSSustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.

Therapy for Obesity Based on Gastrointestinal Hormones

“…Nevertheless, an oxyntomodulin analog with an increased affinity for the glucagon receptor in mice, demonstrated increased potency regarding inhibition of food intake and body weight reduction compared to the native oxyntomodulin [65]. This suggests that this potentiated effect was mediated via the glucagon receptor.…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Further studies have investigated the effects of GLP-1R agonism combined with either glucagon receptor agonism (Pan et al 2006, Day et al 2009 or antagonism (Pocai et al 2009). Although contradictory in nature, these contrasting regimens utilize both the beneficial glucose-lowering effects of GLP-1, combined with either inhibition of glucagon-mediated gluconeogenesis and glycogenolysis (Sinclair & Drucker 2005), and activation of glucagon pathways involved in energy turnover and weight loss (Pocai et al 2009).…”

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

“…The antagonism of glucagon action on the liver also partly mediates the glucose-lowering effect of biguanides (196) . It has been recently demonstrated that the design of peptides with dual agonism for both the glucagon and the GLP-1 receptors is useful to fight against obesity in mice without any apparent adverse effects (197,198) . This is mainly the result of the antihyperglycaemic, lipolytic, satiating and energy expenditure actions of this combined treatment.…”