Open AccessDual melanocortin‐4 receptor and GLP ‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice
Author(s) -
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,
Tschöp Matthias H,
Van der Ploeg Lex HT,
Müller Timo D
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404508
Subject(s) - liraglutide , glucagon like peptide 1 receptor , agonist , endocrinology , melanocortin 4 receptor , medicine , anorectic , receptor , melanocortin , diet induced obese , combination therapy , pharmacology , glucagon receptor , glucagon like peptide 1 , chemistry , diabetes mellitus , type 2 diabetes , insulin , glucagon , insulin resistance , body weight
We assessed the efficacy of simultaneous agonism at the glucagon‐like peptide‐1 receptor ( GLP ‐1R) and the melanocortin‐4 receptor ( MC 4R) 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 MC 4R 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 MC 4R 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 MC 4R and GLP ‐1R agonism for the treatment of obesity and diabetes.