Hepatic fibroblast growth factor 21 is involved in mediating functions of liraglutide in mice with dietary challenge.

Background and aims Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse-hepatocytes; determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide. Approaches and results Liver FGF21 expression was assessed in mice with daily liraglutide injection for 3 days, or in mouse primary hepatocytes (MPH) with direct liraglutide treatment. Effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high fat diet (HFD)-fed mice, in comparison with the DPP-4 inhibitor sitagliptin. Animal studies were also performed in Glp1r-/- mice and hepatic FGF21 knockout (lFgf21-KO) mice. In wild-type mice with RNA-seq and qRT-PCR, we observed liraglutide-stimulated hepatic Fgf21 expression, and the lack of Glp1r expression in mouse liver. In MPH, liraglutide did not stimulate Fgf21. In HFD-induced obese mice, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, while their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated but not sitagliptin-treated mice. In HFD-fed Glp1r-/- mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice on dietary challenge, body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced. Conclusions We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R expressed in extra-hepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding on function of GLP-1-based drugs in nonalcoholic fatty liver disease (NAFLD).