PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats
Authors: N G Abraham
J I Shapiro
D H Kim
L Rodella
K Sodhi
N Puri
D Jude
G Favero
L A Stechschulte
T D Hinds
Journal: International Journal of Obesity (2014)
Discipline: CLINICAL MEDICINE
Keywords: Renin-angiotensin system; PPARδ agonist; oxidative stress; heme oxygenase-1; adipocyte hypertrophy
Affiliations: Department of Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA., Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA., Department of Biomedical Science, Division of Anatomy, University of Brescia, Brescia, Italy.

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. Method: 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&lt;0.05) when compared with sham-operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (P&lt;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&lt;0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (P&lt;0.05). Conclusion: 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. 

Retracted: No

PubPeer comments:
 The expression pattern of the gene is meaningless ![file] The mesonephros is not correctly indicated on the figure ![file] The nomenclature for the central nervous system is wrong. The structure indicated as the trachea is facing the dorsal region of the liver. This is not the correct anatomical location. This is likely a part of the digestive tract. ![file] The structure indicated as the cerebellum is outside the central nervous system. This is probably the cartilage that will give rise to the supra-occipital bone. I am sorry to observe that this expression pattern is of no value. ,