Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets
Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of lir...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-06-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823000522 |
| _version_ | 1827953785963544576 |
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| author | Thao D.V. Le Payam Fathi Amanda B. Watters Blair J. Ellis Gai-Linn K. Besing Nadejda Bozadjieva-Kramer Misty B. Perez Andrew I. Sullivan Jesse P. Rose Laurie L. Baggio Jacqueline Koehler Jennifer L. Brown Michelle B. Bales Kaitlyn G. Nwaba Jonathan E. Campbell Daniel J. Drucker Matthew J. Potthoff Randy J. Seeley Julio E. Ayala |
| author_facet | Thao D.V. Le Payam Fathi Amanda B. Watters Blair J. Ellis Gai-Linn K. Besing Nadejda Bozadjieva-Kramer Misty B. Perez Andrew I. Sullivan Jesse P. Rose Laurie L. Baggio Jacqueline Koehler Jennifer L. Brown Michelle B. Bales Kaitlyn G. Nwaba Jonathan E. Campbell Daniel J. Drucker Matthew J. Potthoff Randy J. Seeley Julio E. Ayala |
| author_sort | Thao D.V. Le |
| collection | DOAJ |
| description | Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. Methods: Circulating FGF21 levels were measured in fasted male C57BL/6J, neuronal GLP-1R knockout, β-cell GLP-1R knockout, and liver peroxisome proliferator-activated receptor alpha knockout mice treated acutely with liraglutide. To test the metabolic relevance of liver FGF21 in response to liraglutide, chow-fed control and liver Fgf21 knockout (LivFgf21−/−) mice were treated with vehicle or liraglutide in metabolic chambers. Body weight and composition, food intake, and energy expenditure were measured. Since FGF21 reduces carbohydrate intake, we measured body weight in mice fed matched diets with low- (LC) or high-carbohydrate (HC) content and in mice fed a high-fat, high-sugar (HFHS) diet. This was done in control and LivFgf21−/− mice and in mice lacking neuronal β-klotho (Klb) expression to disrupt brain FGF21 signaling. Results: Liraglutide increases FGF21 levels independently of decreased food intake via neuronal GLP-1R activation. Lack of liver Fgf21 expression confers resistance to liraglutide-induced weight loss due to attenuated reduction of food intake in chow-fed mice. Liraglutide-induced weight loss was impaired in LivFgf21−/− mice when fed HC and HFHS diets but not when fed a LC diet. Loss of neuronal Klb also attenuated liraglutide-induced weight loss in mice fed HC or HFHS diets. Conclusions: Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in a dietary carbohydrate-dependent manner. |
| first_indexed | 2024-04-09T14:18:57Z |
| format | Article |
| id | doaj.art-d72c33cca2fa47dca8da218c427827be |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-09T14:18:57Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-d72c33cca2fa47dca8da218c427827be2023-05-05T04:40:34ZengElsevierMolecular Metabolism2212-87782023-06-0172101718Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate dietsThao D.V. Le0Payam Fathi1Amanda B. Watters2Blair J. Ellis3Gai-Linn K. Besing4Nadejda Bozadjieva-Kramer5Misty B. Perez6Andrew I. Sullivan7Jesse P. Rose8Laurie L. Baggio9Jacqueline Koehler10Jennifer L. Brown11Michelle B. Bales12Kaitlyn G. Nwaba13Jonathan E. Campbell14Daniel J. Drucker15Matthew J. Potthoff16Randy J. Seeley17Julio E. Ayala18Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Surgery, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Veterans Affairs Ann Arbor Healthcare System, Research Service, 2215 Fuller Road, Ann Arbor, MI 48105, USADepartment of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USADepartment of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USADepartment of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USALunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, CanadaLunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, CanadaDuke Molecular Physiology Institute, Duke University, 300 N. Duke Street, Durham, NC 27701, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USADuke Molecular Physiology Institute, Duke University, 300 N. Duke Street, Durham, NC 27701, USALunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, CanadaDepartment of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USADepartment of Surgery, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USADepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA; Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA; Corresponding author. Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, 742 Robinson Research Building, Nashville, TN 37232, USA.Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. Methods: Circulating FGF21 levels were measured in fasted male C57BL/6J, neuronal GLP-1R knockout, β-cell GLP-1R knockout, and liver peroxisome proliferator-activated receptor alpha knockout mice treated acutely with liraglutide. To test the metabolic relevance of liver FGF21 in response to liraglutide, chow-fed control and liver Fgf21 knockout (LivFgf21−/−) mice were treated with vehicle or liraglutide in metabolic chambers. Body weight and composition, food intake, and energy expenditure were measured. Since FGF21 reduces carbohydrate intake, we measured body weight in mice fed matched diets with low- (LC) or high-carbohydrate (HC) content and in mice fed a high-fat, high-sugar (HFHS) diet. This was done in control and LivFgf21−/− mice and in mice lacking neuronal β-klotho (Klb) expression to disrupt brain FGF21 signaling. Results: Liraglutide increases FGF21 levels independently of decreased food intake via neuronal GLP-1R activation. Lack of liver Fgf21 expression confers resistance to liraglutide-induced weight loss due to attenuated reduction of food intake in chow-fed mice. Liraglutide-induced weight loss was impaired in LivFgf21−/− mice when fed HC and HFHS diets but not when fed a LC diet. Loss of neuronal Klb also attenuated liraglutide-induced weight loss in mice fed HC or HFHS diets. Conclusions: Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in a dietary carbohydrate-dependent manner.http://www.sciencedirect.com/science/article/pii/S2212877823000522Glucagon-like peptide-1 receptor agonistsFibroblast growth factor-21LiraglutideCarbohydrateFood intakeWeight loss |
| spellingShingle | Thao D.V. Le Payam Fathi Amanda B. Watters Blair J. Ellis Gai-Linn K. Besing Nadejda Bozadjieva-Kramer Misty B. Perez Andrew I. Sullivan Jesse P. Rose Laurie L. Baggio Jacqueline Koehler Jennifer L. Brown Michelle B. Bales Kaitlyn G. Nwaba Jonathan E. Campbell Daniel J. Drucker Matthew J. Potthoff Randy J. Seeley Julio E. Ayala Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets Molecular Metabolism Glucagon-like peptide-1 receptor agonists Fibroblast growth factor-21 Liraglutide Carbohydrate Food intake Weight loss |
| title | Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| title_full | Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| title_fullStr | Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| title_full_unstemmed | Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| title_short | Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| title_sort | fibroblast growth factor 21 is required for weight loss induced by the glucagon like peptide 1 receptor agonist liraglutide in male mice fed high carbohydrate diets |
| topic | Glucagon-like peptide-1 receptor agonists Fibroblast growth factor-21 Liraglutide Carbohydrate Food intake Weight loss |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823000522 |
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