Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of 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; 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:10.1101/2023.01.03.522509

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Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets

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Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of 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, Nadejda Bozadjieva-Kramer, Misty B Perez, Andrew I Sullivan, Jesse P Rose, Laurie L Baggio, Jacqueline Koehler, …

bioRxiv : the preprint server for biology

01/03/2023

DOI: 10.1101/2023.01.03.522509

PMCID: PMC9881863

PMID: 36711605

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https://doi.org/10.1101/2023.01.03.522509View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. We show that liraglutide increases FGF21 levels via neuronal GLP-1R activation. We also demonstrate that lack of liver expression confers partial resistance to liraglutide-induced weight loss. Since FGF21 reduces carbohydrate intake, we tested whether the contribution of FGF21 to liraglutide-induced weight loss is dependent on dietary carbohydrate content. In control and liver knockout (Liv ) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed Liv mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in Liv mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal β-klotho expression also diminishes liraglutide-induced weight loss in mice fed a HC or HFHS diet, indicating that FGF21 mediates liraglutide-induced weight loss via neuronal FGF21 action. Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in the presence of high dietary carbohydrate content.

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Title: Subtitle: Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets
Creators: Thao D V Le
Payam Fathi
Amanda B Watters
Blair J Ellis
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
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.01.03.522509
PMID: 36711605
PMCID: PMC9881863
Language: English
Date posted: 01/03/2023
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984363657702771

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