title: Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway.
abstract: Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1α. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1α-signaling pathway.
  
  
  CONCLUSIONS
  Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases.
authors.affiliation: Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China. zhoulei@mail.hzau.edu.cn
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yu
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Meng
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Li
authors.forename: Congcong
authors.initials: C
authors.lastname: Niu
authors.forename: Yun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Cai
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Chaoqiang
authors.initials: C
authors.lastname: An
authors.forename: Le
authors.initials: L
authors.lastname: Shu
authors.forename: Ao
authors.initials: A
authors.lastname: Chen
authors.forename: Handong
authors.initials: H
authors.lastname: Su
authors.forename: Yin
authors.initials: Y
authors.lastname: Tang
authors.forename: Shen
authors.initials: S
authors.lastname: Yin
authors.forename: Silja
authors.initials: S
authors.lastname: Raschke
authors.forename: Kristin
authors.initials: K
authors.lastname: Eckardt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eckel
authors.forename: Zaiqing
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000139:chemically induced* / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011493:Protein Kinase C / Q000502:physiology*; D052243:Resistin / Q000009:adverse effects* / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D052243:Resistin; D015534:Trans-Activators; D014157:Transcription Factors; D019892:eIF-2 Kinase; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C