title: Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice.
abstract: Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte-autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21-deficient mice display pronounced insulin-stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin- or nutrient-stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21-mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic βKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin-sensitizing and glycemic-control effects of FGF21 in diet-induced insulin-resistant mice. Moreover, FGF21 improves methionine- and choline-deficient diet-induced steatohepatitis.
  
  
  
  FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes. (Hepatology 2016;64:425-438).
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Aoyuan
authors.initials: A
authors.lastname: Cui
authors.affiliation: Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Haoyang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China.
authors.forename: Xuqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Qingning
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Ye
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|Department of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D013395:Sucrose; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007328:Insulin; C418622:Klb protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C414620:fibroblast growth factor 21; D013395:Sucrose; D005346:Fibroblast Growth Factors; D006003:Glycogen; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000090265:Klotho Proteins