title: Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice.
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.
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Christoffer
authors: C
authors: Clemmensen
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Brian
authors: B
authors: Finan
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Katrin
authors: K
authors: Fischer
authors: Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors: Robby Zachariah
authors: RZ
authors: Tom
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Beata
authors: B
authors: Legutko
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Laura
authors: L
authors: Sehrer
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Daniela
authors: D
authors: Heine
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Niklas
authors: N
authors: Grassl
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Carola W
authors: CW
authors: Meyer
authors: Rhythm, Boston, Massachusetts, USA.
authors: Bart
authors: B
authors: Henderson
authors: Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors: Susanna M
authors: SM
authors: Hofmann
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors: Matthias H
authors: MH
authors: Tschöp
authors: Rhythm, Boston, Massachusetts, USA.
authors: Lex H T
authors: LH
authors: Van der Ploeg
authors: Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Neuherberg, Germany Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany timo.mueller@helmholtz-muenchen.de.
authors: Timo D
authors: TD
authors: Müller
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069450:Liraglutide; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D018027:Receptors, Glucagon / Q000819:agonists*; D016896:Treatment Outcome; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D044105:Receptor, Melanocortin, Type 4; D018027:Receptors, Glucagon; C579663:setmelanotide; D000521:alpha-MSH; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: Glp‐1r; Mc4r; diabetes; liraglutide; obesity
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