Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice
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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.
Original language | English |
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Journal | EMBO Molecular Medicine |
Volume | 7 |
Issue number | 3 |
Pages (from-to) | 288-98 |
Number of pages | 11 |
ISSN | 1757-4676 |
DOIs | |
Publication status | Published - Mar 2015 |
- Animals, Diabetes Mellitus, Drug Synergism, Drug Therapy, Combination, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Hypoglycemic Agents, Liraglutide, Mice, Obese, Obesity, Receptor, Melanocortin, Type 4, Receptors, Glucagon, Treatment Outcome, alpha-MSH, Journal Article, Research Support, Non-U.S. Gov't
Research areas
ID: 186640302