title: Enhancement of hypothalamic STAT3 acetylation by nuclear receptor Nur77 dictates leptin sensitivity.
abstract: Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aging-induced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Hang-Zi
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: He
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Xian-Wen
authors.initials: XW
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Wan
authors.affiliation: Department of Neurosurgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Neuroscience, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Shanghai Province, China.
authors.forename: Shu-Jing
authors.initials: SJ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Neuroscience, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Shanghai Province, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China qiaow@xmu.edu.cn.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D020738:Leptin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D020738:Leptin; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D050796:STAT3 Transcription Factor