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

EMBO Molecular Medicine

Christoffer Clemmensen²  Brian Finan²  Katrin Fischer²  Robby Zachariah Tom¹  Beata Legutko²  Laura Sehrer²  Daniela Heine²  Niklas Grassl²  Carola W Meyer²  Bart Henderson³  Susanna M Hofmann¹  Matthias H Tschöp²  Lex HT Van der Ploeg³ 

[1] Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany;Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany;Rhythm, Boston, Massachusetts, USA

关键词: diabetes;    Glp‐1r;    liraglutide;    Mc4r;    obesity;   

DOI  :  10.15252/emmm.201404508

来源: Wiley

【 摘 要 】

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.

Synopsis

Combination therapy with a melanocortin-4 receptor agonist (RM-493) and a GLP-1 receptor agonist (liraglutide) potently reversed obesity, dyslipidemia and glucose metabolic perturbations in diet-induced obese mice chronically maintained on a high-fat, high-sugar diet.

• RM-493 and liraglutide co-treatment amplifies weight loss and improves glucose and lipid metabolism beyond that of either compound used as a mono-therapy.
• MC4R-agonism enhances GLP-1R signaling in the hypothalamus.
• Dual MC4R and GLP-1R agonism improves insulin signaling and cholesterol metabolism in the liver.
• This poly-pharmacological treatment holds promise as a novel opportunity for treating diet-induced metabolic disorders.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.