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

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 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. ### Competing Interest Statement Daniel Drucker has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, Kallyope, Merck Research Laboratories, Novo Nordisk Inc., and Pfizer Inc. Investigator-initiated research in the Drucker lab is supported in part by funding from Novo Nordisk and Pfizer Inc to Mt. Sinai Hospital. Neither Dr. Drucker or his family members hold issued stock directly or indirectly in any of these companies. Dr. Drucker holds non-exercised options in Kallyope. Randy Seeley has served as a consultant or on the Scientific Advisory Board for Novo Nordisk, Scohia, CinRx, Fractyl, and Structure Therapeutics and has equity in Calibrate and Rewind. The Seeley lab is supported in part by funding from Novo Nordisk, Astra Zeneca, Fractyl, and Eli Lilly. The Campbell lab is supported in part by funding from Eli Lilly, Merck, and Novo Nordisk.