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

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.

• Authors: Christoffer Clemmensen, Brian Finan, Katrin Fischer, Robby Zachariah Tom, Beata Legutko, Laura Sehrer, Daniela Heine, Niklas Grassl, Carola W Meyer, Bart Henderson, Susanna M Hofmann, Matthias H Tschöp, Lex H T Van der Ploeg, Timo D Müller
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 7 Issue 3 Pg. 288-98 (Mar 2015) ISSN: 1757-4684 [Electronic] England
• PMID: 25652173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Receptor, Melanocortin, Type 4
• Receptors, Glucagon
• setmelanotide
• alpha-MSH
• Liraglutide
• Glucagon-Like Peptide 1

Topics

• Animals
• Diabetes Mellitus (drug therapy)
• Drug Synergism
• Drug Therapy, Combination
• Glucagon-Like Peptide 1 (analogs & derivatives, pharmacology, therapeutic use)
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Liraglutide
• Mice, Obese
• Obesity (drug therapy)
• Receptor, Melanocortin, Type 4 (agonists)
• Receptors, Glucagon (agonists)
• Treatment Outcome
• alpha-MSH (analogs & derivatives, pharmacology, therapeutic use)