1. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice
- Author
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Gary G. Chicchi, Michael E. Lassman, Lan Zhu, Michael M. Sountis, George J. Eiermann, Xiaobing Du, Antonello Pessi, Alessandro Pocai, Nancy A. Thornberry, Xiaoping Zhang, Paul E. Carrington, Ranabir SinhaRoy, Jennifer R. Adams, Elisabetta Bianchi, Michael Wright, Guoqiang Jiang, Corey N. Miller, Gaochao Zhou, Franklin Liu, Laurie Tota, Donald J. Marsh, Aleksandr Petrov, Alessia Santoprete, and Elena Capito
- Subjects
Agonist ,medicine.medical_specialty ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Injections, Subcutaneous ,Molecular Sequence Data ,CHO Cells ,Biology ,Glucagon ,Glucagon-Like Peptide-1 Receptor ,chemistry.chemical_compound ,Mice ,Cricetulus ,Glucagon-Like Peptide 1 ,Internal medicine ,Cricetinae ,Weight Loss ,Internal Medicine ,medicine ,Receptors, Glucagon ,Animals ,Insulin ,Amino Acid Sequence ,Obesity ,Receptor ,Adiponectin ,Reverse Transcriptase Polymerase Chain Reaction ,Leptin ,Body Weight ,Glucagon-like peptide-1 ,Dietary Fats ,Oxyntomodulin ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Original Article ,Energy Intake ,Glucagon receptor ,Obesity Studies - Abstract
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.
- Published
- 2009