RNA-Seq analysis on the liver of mice treated with high-fat diet and liraglutide

GLP-1 based diabetes drugs are effective to reduce hepatic lipid accumulation beyong glycemic control. As GLP-1 receptor (GLP-1R) is not expressed in hepatocytes, the mechanism behind the beneficial effects of GLP-1 based drugs on the liver remained elusive. Several studies have shown that the expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based drugs. Therefore, the present study aimed to assess such stimulation in mice and in mouse primary hepatocytes, determine whether hepatic FGF21 mediates functions of the GLP-1R agonist liraglutide, and to explore the potential mechanisms of liraglutide regulating the expression of FGF21. In high-fat diet induced obese mice, we observed hepatic and plasma FGF21 elevation, improved glucose disposal, and reduced plasma triglyceride levels by liraglutide treatment. Moreover, RNA-sequencing on the liver suggested that Fgf21 was the most upregulated gene after liraglutide treatment. In liver-specific FGF21 knock-out mice on high-fat and high-fructose diet, the body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced. These studies implied that hepatic FGF21 was the critical mediator of liraglutide-induced metabolic improvement. Overall design: RNA was isolated from liver of mice treated with high-fat diet for 4 weeks and then subcutaneously injected with liraglutide at 300 µg/kg body weight for 3 days.