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

Le, T. D. V.; Fathi, P.; Watters, A. B.; Ellis, B. J.; Bozadjieva-Kramer, N.; Perez, M. B.; Sullivan, A. I.; Rose, J. P.; Baggio, L. L.; Koehler, J.; Brown, J. L.; Bales, M. B.; Nwaba, K. G.; Campbell, J. E.; Drucker, D. J.; Potthoff, M. J.; Seeley, R. J.; Ayala, J. E.

doi:10.1101/2023.01.03.522509

bioRxiv · 10.1101/2023.01.03.522509

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

Le, T. D. V.·Fathi, P.·Watters, A. B.·Ellis, B. J.·Bozadjieva-Kramer, N.·Perez, M. B.·Sullivan, A. I.·Rose, J. P.·Baggio, L. L.·Koehler, J.·Brown, J. L.·Bales, M. B.·Nwaba, K. G.·Campbell, J. E.·Drucker, D. J.·Potthoff, M. J.·Seeley, R. J.·Ayala, J. E.

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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 Fgf21 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 Fgf21 knockout (LivFgf21-/-) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed LivFgf21-/- mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in LivFgf21-/- mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal {beta}-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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Le, T. D. V., Fathi, P., Watters, A. B., Ellis, B. J., Bozadjieva-Kramer, N., Perez, M. B., Sullivan, A. I., Rose, J. P., Baggio, L. L., Koehler, J., Brown, J. L., Bales, M. B., Nwaba, K. G., Campbell, J. E., Drucker, D. J., Potthoff, M. J., Seeley, R. J., Ayala, J. E.. 2023-01-04. 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. https://doi.org/10.1101/2023.01.03.522509

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