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

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

doi:10.1016/j.molmet.2023.101718

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

Mol Metab. 2023 Jun:72:101718. doi: 10.1016/j.molmet.2023.101718. Epub 2023 Apr 7.

Authors

Thao D V Le¹, Payam Fathi², Amanda B Watters³, Blair J Ellis⁴, Gai-Linn K Besing⁵, Nadejda Bozadjieva-Kramer⁶, Misty B Perez⁷, Andrew I Sullivan⁸, Jesse P Rose⁹, Laurie L Baggio¹⁰, Jacqueline Koehler¹¹, Jennifer L Brown¹², Michelle B Bales¹³, Kaitlyn G Nwaba⁴, Jonathan E Campbell¹⁴, Daniel J Drucker¹⁵, Matthew J Potthoff¹⁶, Randy J Seeley¹⁷, Julio E Ayala¹⁸

Affiliations

¹ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA. Electronic address: thao.d.le@vanderbilt.edu.
² Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA. Electronic address: payam.fathi@vanderbilt.edu.
³ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA. Electronic address: awatters@tulane.edu.
⁴ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.
⁵ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA. Electronic address: gai-linn.besing.1@vanderbilt.edu.
⁶ Department 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, USA. Electronic address: nibozad@med.umich.edu.
⁷ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USA. Electronic address: misty-perez@uiowa.edu.
⁸ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USA. Electronic address: andrew-sullivan-1@uiowa.edu.
⁹ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USA. Electronic address: jesse-rose@uiowa.edu.
¹⁰ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Electronic address: baggio@lunenfeld.ca.
¹¹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
¹² Duke Molecular Physiology Institute, Duke University, 300 N. Duke Street, Durham, NC 27701, USA.
¹³ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA. Electronic address: bales@psy.fsu.edu.
¹⁴ Duke Molecular Physiology Institute, Duke University, 300 N. Duke Street, Durham, NC 27701, USA. Electronic address: jonathan.campbell@duke.edu.
¹⁵ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Electronic address: drucker@lunenfeld.ca.
¹⁶ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 375 Newton Road, Iowa City, IA 52242, USA. Electronic address: matthew-potthoff@uiowa.edu.
¹⁷ Department of Surgery, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: seeleyrj@med.umich.edu.
¹⁸ Department 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. Electronic address: julio.e.ayala@vanderbilt.edu.

Abstract

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 (Liv^Fgf21-/-) 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 Liv^Fgf21-/- 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 Liv^Fgf21-/- 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.

Keywords: Carbohydrate; Fibroblast growth factor-21; Food intake; Glucagon-like peptide-1 receptor agonists; Liraglutide; Weight loss.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carbohydrates
Diet, High-Fat
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism
Glucagon-Like Peptide-1 Receptor* / metabolism
Liraglutide* / pharmacology
Male
Mice
Mice, Inbred C57BL
Weight Loss

Substances

Carbohydrates
fibroblast growth factor 21
Fibroblast Growth Factors
Glucagon-Like Peptide-1 Receptor
Liraglutide

Abstract

Publication types

MeSH terms

Substances

Grants and funding