title: 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.
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Tong-Yan
authors: TY
authors: Liu
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Xiao-Qing
authors: XQ
authors: Xiong
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Xing-Sheng
authors: XS
authors: Ren
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Ming-Xia
authors: MX
authors: Zhao
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Chang-Xiang
authors: CX
authors: Shi
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Jue-Jin
authors: JJ
authors: Wang
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Ye-Bo
authors: YB
authors: Zhou
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Feng
authors: F
authors: Zhang
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Ying
authors: Y
authors: Han
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Xing-Ya
authors: XY
authors: Gao
authors: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Qi
authors: Q
authors: Chen
authors: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Yue-Hua
authors: YH
authors: Li
authors: Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors: Yu-Ming
authors: YM
authors: Kang
authors: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China gqzhucn@njmu.edu.cn.|Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Guo-Qing
authors: GQ
authors: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D005353:Fibronectins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C577593:FNDC5 protein, human; D005353:Fibronectins; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases