title: Endoplasmic reticulum stress regulates adipocyte resistin expression.
abstract: OBJECTIVE
  Resistin is a secreted polypeptide that impairs glucose metabolism and, in rodents, is derived exclusively from adipocytes. In murine obesity, resistin circulates at elevated levels but its gene expression in adipose tissue is paradoxically reduced. The mechanism behind the downregulation of resistin mRNA is poorly understood. We investigated whether endoplasmic reticulum (ER) stress, which is characteristic of obese adipose tissue, regulates resistin expression in cultured mouse adipocytes.
  
  
  METHODS
  The effects of endoplasmic stress inducers on resistin mRNA and secreted protein levels were examined in differentiated 3T3-L1 adipocytes, focusing on the expression and genomic binding of transcriptional regulators of resistin. The association between downregulated resistin mRNA and induction of ER stress was also investigated in the adipose tissue of mice fed a high-fat diet.
  
  
  RESULTS
  ER stress reduced resistin mRNA in 3T3-L1 adipocytes in a time- and dose-dependent manner. The effects of ER stress were transcriptional because of downregulation of CAAT/enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma transcriptional activators and upregulation of the transcriptional repressor CAAT/enhancer binding protein homologous protein-10 (CHOP10). Resistin protein was also substantially downregulated, showing a close correspondence with mRNA levels in 3T3-L1 adipocytes as well as in the fat pads of obese mice.
  
  
  CONCLUSIONS
  ER stress is a potent regulator of resistin, suggesting that ER stress may underlie the local downregulation of resistin mRNA and protein in fat in murine obesity. The paradoxical increase in plasma may be because of various systemic abnormalities associated with obesity and insulin resistance.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Martina I
authors.initials: MI
authors.lastname: Lefterova
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Takuya
authors.initials: T
authors.lastname: Tomaru
authors.forename: Mohammed
authors.initials: M
authors.lastname: Qatanani
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D041721:3T3-L1 Cells / Q000502:physiology; D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004822:Epididymis; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D052243:Resistin / Q000235:genetics*; D014162:Transfection
chemical_list: D004041:Dietary Fats; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D052243:Resistin; D008156:Luciferases