Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice

Nov 4, 2021Laboratory investigation; a journal of technical methods and pathology

Increasing liver production of fibroblast growth factor 21 reduces obesity and fatty liver caused by a high-fat diet in mice

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Abstract

Hydrodynamic injection of FGF21 every 6 weeks resulted in marked reductions in body weight and liver steatosis in high-fat diet-fed mice.

FGF21 is mainly secreted by the liver and is influenced by ketogenic diets and alcohol consumption.
The treatment led to reductions in epididymal fat mass and insulin resistance.
Hepatic expression of genes related to gluconeogenesis and lipogenesis was significantly suppressed.
FGF21 activated specific signaling pathways that downregulated mTORC1 signaling.
Increased expression of proteins involved in ketone body metabolism was observed in skeletal muscle.
The findings suggest that FGF21 may facilitate energy use and contribute to liver health.

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Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.

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Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice

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