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EMBO Mol Med. 2015 Mar;7(3):288-98. doi: 10.15252/emmm.201404508.

Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice.

Author information

1
Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
2
Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
3
Rhythm, Boston, Massachusetts, USA.
4
Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany timo.mueller@helmholtz-muenchen.de.

Abstract

We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.

KEYWORDS:

Glp‐1r; Mc4r; diabetes; liraglutide; obesity

PMID:
25652173
PMCID:
PMC4364946
DOI:
10.15252/emmm.201404508
[Indexed for MEDLINE]
Free PMC Article

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