FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice

Abstract

Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat and mediates the 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 the liver compared with wild-type mice. Energy deprivation-induced autophagy, FAO, and AMPK activity were attenuated in FNDC5 hepatocytes, which were restored by activating AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Inhibition of mammalian target of rapamycin (mTOR) complex 1 with rapamycin enhanced autophagy and FAO and 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 the AMPK/mTOR pathway. FNDC5 deficiency aggravates whereas FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in the liver.

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation

“…1A). Efficiency of FNDC5 gene deletion has been identified in our recent study [25], and was further confirmed by the disappeared FNDC5 mRNA and protein expressions in the present study (Fig. 1A).…”

“…We have shown that either FNDC5 overexpression or irisin ameliorates glucose/lipid metabolic derangements and enhances lipolysis in obesity [12]. Moreover, FNDC5 alleviates hepatosteatosis by restoring AMPK/mTOR-mediated autophagy, fatty acid oxidation, and lipogenesis in mice [13]. However, whether FNDC5 is involved in the process of liver fibrosis is unknown.…”

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

“…Moreover, it has been reported that exercise-stimulated release of irisin is independent of age or fitness level [49], although there are differences in the basal circulating irisin levels [48,49]. Accumulating evidence have shown that irisin exhibits protective effects on glucose homeostasis in obesity and T2DM, probably via the modulation of glucose and lipid metabolism in hepatic tissue and skeletal muscle [11,12,50,51]. The present study extends the previous findings via demonstrating the protective action of irisin on β-cell lipid metabolism and inflammation under type 2 diabetic condition.…”

“…In this regard, the circulating levels of irisin were found to be altered in obese individuals and diabetic patients [8]; these levels were considered to be one biomarker for the prediction of the development of diabetes and mortality risk of cardiovascular diseases [9,10]. We and others have demonstrated that, in an overnutrition state, irisin can restore metabolic homeostasis, thereby alleviating insulin resistance and protecting cell function as well as survival in hepatic tissues [11][12][13]. For instance, irisin attenuated PA-induced excessive lipid accumulation in hepatocytes [13], while deficiency of FNDC5 exacerbated hepatic lipogenesis and lipid accumulation in obese mice [11].…”

“…We and others have demonstrated that, in an overnutrition state, irisin can restore metabolic homeostasis, thereby alleviating insulin resistance and protecting cell function as well as survival in hepatic tissues [11][12][13]. For instance, irisin attenuated PA-induced excessive lipid accumulation in hepatocytes [13], while deficiency of FNDC5 exacerbated hepatic lipogenesis and lipid accumulation in obese mice [11].…”