Author:
Le Thao D. V.,Fathi Payam,Watters Amanda B.,Ellis Blair J.,Bozadjieva-Kramer Nadejda,Perez Misty B.,Sullivan Andrew I.,Rose Jesse P.,Baggio Laurie L.,Koehler Jacqueline,Brown Jennifer L.,Bales Michelle B.,Nwaba Kaitlyn G.,Campbell Jonathan E.,Drucker Daniel J.,Potthoff Matthew J.,Seeley Randy J.,Ayala Julio E.
Abstract
AbstractGlucagon-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 liverFgf21expression 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 liverFgf21knockout (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.
Publisher
Cold Spring Harbor Laboratory