title: PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.
abstract: OBJECTIVE
  Renin-angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-δ (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model.
  
  
  METHODS
  We first established a direct stimulatory effect of the PPARδ agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. Sprague-Dawley rats were divided into four groups: sham-operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP).
  
  
  RESULTS
  2K1C animals had increased visceral adiposity, adipocyte hypertrophy, increased inflammatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (P<0.05) when compared with sham-operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (P<0.01) along with enhancement of Wnt10b and β-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt5b, mesoderm specific transcript (mest) and C/EBPα levels and an increased number of small adipocytes (P<0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (P<0.05).
  
  
  CONCLUSIONS
  Taken together, our study demonstrates, for the first time, that increased levels of Ang II contribute towards adipose tissue dysregulation, which is abated by PPARδ-mediated upregulation of the heme-HO system. These findings highlight the pivotal role and symbiotic relationship of HO-1, adiponectin and PPARδ in the regulation of metabolic homeostasis in adipose tissues.
authors.affiliation: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sodhi
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Puri
authors.affiliation: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Stechschulte
authors.affiliation: Department of Biomedical Science, Division of Anatomy, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Favero
authors.affiliation: Department of Biomedical Science, Division of Anatomy, University of Brescia, Brescia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rodella
authors.affiliation: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Shapiro
authors.affiliation: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jude
authors.affiliation: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006978:Hypertension, Renovascular / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood
chemical_list: D047494:PPAR delta; D000804:Angiotensin II; D051547:Heme Oxygenase-1; D012083:Renin