Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat, and mediates beneficial effects of exercise on metabolism. However, whether FNDC5 is associated with hepatic steatosis, autophagy, fatty acid oxidation (FAO) and lipogenesis remains unknown. Herein, we show the roles and mechanisms of FNDC5 in hepatic steatosis, autophagy and lipid metabolism. Fasted FNDC5-/- mice exhibited severe steatosis, reduced autophagy and FAO, and enhanced lipogenesis in liver compared with WT mice. Energy deprivation induced autophagy, FAO and AMPK activity were attenuated in FNDC5-/- hepatocytes, which were restored by activating AMPK with AICAR. Inhibition of mTORC1 with rapamycin enhanced autophagy and FAO, attenuated lipogenesis and steatosis in FNDC5-/- livers. FNDC5 deficiency exacerbated hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis and lipid accumulation in obese mice. Exogenous FNDC5 stimulated autophagy and FAO gene expression in hepatocytes, and repaired the attenuated autophagy and palmitate-induced steatosis in FNDC5-/- hepatocytes. FNDC5 overexpression prevented hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis and lipid accumulation in obese mice. These results indicate that FNDC5 deficiency impairs autophagy and FAO, and enhances lipogenesis via AMPK/mTOR pathway. FNDC5 deficiency aggravates while FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in liver.
- Received March 17, 2016.
- Accepted July 21, 2016.
- © 2016 by the American Diabetes Association.