TY - JOUR

T1 - Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice

AU - Clemmensen, Christoffer

AU - Finan, Brian

AU - Fischer, Katrin

AU - Tom, Robby Zachariah

AU - Legutko, Beata

AU - Sehrer, Laura

AU - Heine, Daniela

AU - Grassl, Niklas

AU - Meyer, Carola W

AU - Henderson, Bart

AU - Hofmann, Susanna M

AU - Tschöp, Matthias H

AU - Van der Ploeg, Lex H T

AU - Müller, Timo D

N1 - © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

KW - Animals

KW - Diabetes Mellitus

KW - Drug Synergism

KW - Drug Therapy, Combination

KW - Glucagon-Like Peptide 1

KW - Glucagon-Like Peptide-1 Receptor

KW - Hypoglycemic Agents

KW - Liraglutide

KW - Mice, Obese

KW - Obesity

KW - Receptor, Melanocortin, Type 4

KW - Receptors, Glucagon

KW - Treatment Outcome

KW - alpha-MSH

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.15252/emmm.201404508

DO - 10.15252/emmm.201404508

M3 - Journal article

C2 - 25652173

VL - 7

SP - 288

EP - 298

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 3

ER -