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

作者：Clemmensen Christoffer; Finan Brian; Fischer Katrin; Tom Robby Zachariah; Legutko Beata; Sehrer Laura; Heine Daniela; Grassl Niklas; Meyer Carola W; Henderson Bart; Hofmann Susanna M; Tschoep Matthias H; Van der Ploeg Lex H T; Mueller Timo D

来源：EMBO Molecular Medicine, 2015, 7(3): 288-298.

DOI：10.15252/emmm.201404508

• diabetes
• Glp-1r
• liraglutide
• Mc4r
• obesity

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.

• 出版日期2015-3