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 li...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201404508 |
| _version_ | 1827015169577844736 |
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| author | Christoffer Clemmensen Brian Finan Katrin Fischer Robby Zachariah Tom Beata Legutko Laura Sehrer Daniela Heine Niklas Grassl Carola W Meyer Bart Henderson Susanna M Hofmann Matthias H Tschöp Lex HT Van der Ploeg Timo D Müller |
| author_facet | Christoffer Clemmensen Brian Finan Katrin Fischer Robby Zachariah Tom Beata Legutko Laura Sehrer Daniela Heine Niklas Grassl Carola W Meyer Bart Henderson Susanna M Hofmann Matthias H Tschöp Lex HT Van der Ploeg Timo D Müller |
| author_sort | Christoffer Clemmensen |
| collection | DOAJ |
| description | 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. |
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| id | doaj.art-c1558d4a607f4a25a4ebf5a0ff08660d |
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| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:14Z |
| publishDate | 2015-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c1558d4a607f4a25a4ebf5a0ff08660d2024-10-28T08:58:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-02-017328829810.15252/emmm.201404508Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese miceChristoffer Clemmensen0Brian Finan1Katrin Fischer2Robby Zachariah Tom3Beata Legutko4Laura Sehrer5Daniela Heine6Niklas Grassl7Carola W Meyer8Bart Henderson9Susanna M Hofmann10Matthias H Tschöp11Lex HT Van der Ploeg12Timo D Müller13Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)RhythmInstitute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)RhythmInstitute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)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.https://doi.org/10.15252/emmm.201404508diabetesGlp‐1rliraglutideMc4robesity |
| spellingShingle | Christoffer Clemmensen Brian Finan Katrin Fischer Robby Zachariah Tom Beata Legutko Laura Sehrer Daniela Heine Niklas Grassl Carola W Meyer Bart Henderson Susanna M Hofmann Matthias H Tschöp Lex HT Van der Ploeg Timo D Müller Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice EMBO Molecular Medicine diabetes Glp‐1r liraglutide Mc4r obesity |
| title | Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice |
| title_full | Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice |
| title_fullStr | Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice |
| title_full_unstemmed | Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice |
| title_short | Dual melanocortin‐4 receptor and GLP‐1 receptor agonism amplifies metabolic benefits in diet‐induced obese mice |
| title_sort | dual melanocortin 4 receptor and glp 1 receptor agonism amplifies metabolic benefits in diet induced obese mice |
| topic | diabetes Glp‐1r liraglutide Mc4r obesity |
| url | https://doi.org/10.15252/emmm.201404508 |
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