title: The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy.
abstract: BACKGROUND
  Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-β), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown.
  
  
  METHODS
  Regulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR.
  
  
  RESULTS
  Adiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ.
  
  
  CONCLUSIONS
  These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Zenshiro
authors.initials: Z
authors.lastname: Tamaki
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Roberta G
authors.initials: RG
authors.lastname: Marangoni
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Ross S
authors.initials: RS
authors.lastname: Summer
authors.forename: Boping
authors.initials: B
authors.lastname: Ye
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000199:Actins / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D052242:Adiponectin; D047495:PPAR gamma; D016212:Transforming Growth Factor beta; D003094:Collagen; D000263:Adenylate Kinase