title: Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism.
abstract: Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5'-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Li
authors.initials: L
authors.lastname: Mo
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Qinhui
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Jiangying
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Shiyun
authors.initials: S
authors.lastname: Pu
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Shihai
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Min
authors.initials: M
authors.lastname: Zou
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.affiliation: Center of Gerontology and Geriatrics (L.M.), Department of Pharmacy (J.S., J.K., S.P., S.C., M.Z., J.H.), Laboratory of Clinical Pharmacy and Adverse Drug Reaction (Q.L., J.H.), Division of Endocrinology and Metabolism (Y.Z.), Molecular Medicine Research Center (W.J.), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China; Department of Physiology and Pathophysiology (C.J.), School of Basic Medical Sciences, Peking University, Beijing 100871; and Department of Physiology and Pathophysiology (A.Q.), School of Basic Medical Sciences, Capital Medical University, Beijing 100069.
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D000090702:Constitutive Androstane Receptor; D059305:Diet, High-Fat; D005353:Fibronectins / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009688:Nuclear Reactors; D009765:Obesity / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; C571428:FNDC5 protein, mouse; D005353:Fibronectins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000249:Adenosine Monophosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose