title: Hepatic Oncostatin M Receptor β Regulates Obesity-Induced Steatosis and Insulin Resistance.
abstract: The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor β chain (OSMRβ) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMRβ in metabolic disorders remains unclear. Here, we report on the central role of OSMRβ in the protection against obesity and deregulation of glucose and lipids. We observed significantly varied expression levels of OSMRβ in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMRβ displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMRβ. Mechanistically, we showed that OSMRβ phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the liver. More importantly, the liver-restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMRβ knockout mice, whereas OSMRβ overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMRβ-mediated beneficial effects. In conclusion, hepatic OSMRβ expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades.
authors.affiliation: Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zuo-Zhi
authors.initials: ZZ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China; College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Qin
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Sijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China. Electronic address: lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D017353:Gene Deletion; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008099:Liver / Q000502:physiology; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D009765:Obesity / Q000150:complications*; D053681:Oncostatin M Receptor beta Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors
chemical_list: D001786:Blood Glucose; D053681:Oncostatin M Receptor beta Subunit; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2