Journal article
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 (Germany), Vol.72, 101718
04/07/2023
DOI: 10.1016/j.molmet.2023.101718
PMCID: PMC10131131
PMID: 37030441
Abstract
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.
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.
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.
Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in a dietary carbohydrate-dependent manner.
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•The GLP-1 receptor agonist liraglutide increases circulating FGF21 levels.•Liraglutide-induced FGF21 reduces weight only in mice fed high carbohydrate diets.•Weight lowering by liraglutide-induced FGF21 is via neuronal FGF21 action.
Details
- Title: Subtitle
- 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
- Creators
- Thao D.V. Le - Vanderbilt UniversityPayam Fathi - Vanderbilt UniversityAmanda B. Watters - Tulane UniversityBlair J. Ellis - Vanderbilt UniversityGai-Linn K. Besing - Vanderbilt UniversityNadejda Bozadjieva-Kramer - VA Ann Arbor Healthcare SystemMisty B. Perez - University of IowaAndrew I. Sullivan - University of IowaJesse P. Rose - University of IowaLaurie L. Baggio - Lunenfeld-Tanenbaum Research InstituteJacqueline Koehler - Lunenfeld-Tanenbaum Research InstituteJennifer L. Brown - Duke UniversityMichelle B. Bales - Florida State UniversityKaitlyn G. Nwaba - Vanderbilt UniversityJonathan E. Campbell - Duke UniversityDaniel J. Drucker - Lunenfeld-Tanenbaum Research InstituteMatthew J. Potthoff - University of IowaRandy J. Seeley - University of MichiganJulio E. Ayala - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.72, 101718
- DOI
- 10.1016/j.molmet.2023.101718
- PMID
- 37030441
- PMCID
- PMC10131131
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- Elsevier GmbH
- Language
- English
- Date published
- 04/07/2023
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984388758102771
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