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

Jul 16, 2009Diabetes

Activating both GLP-1 and glucagon receptors reverses obesity in mice

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Abstract

Peptide DualAG shows superior weight loss and lipid-lowering activity compared to the GLP1R-selective agonist GLPAG.

Chronic treatment with DualAG led to greater reductions in body weight and improved metabolic parameters such as insulin, leptin, and adiponectin compared to GLPAG.
Both weight loss and lipid-lowering effects were associated with increased fatty acid oxidation and reduced liver fat in diet-induced obese mice.
The antiobesity effects of DualAG depend on the activation of both the GLP-1 and glucagon receptors.

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OBJECTIVE: Oxyntomodulin (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 METHODS: We 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.

RESULTS: Peptide 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.

CONCLUSIONS: Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.

Key numbers

25%

Weight Loss Reduction

Weight loss after 14 days of treatment with DualAG.

30%

Food Intake Reduction

Cumulative food intake reduction with DualAG treatment.

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

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