RETRACTED ARTICLE: PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats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.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<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).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.

Redox modulation of adipocyte differentiation: hypothesis of “Redox Chain” and novel insights into intervention of adipogenesis and obesity

“…In addition, over-expression of HO-1 increases pAMPK and eNOS levels and promotes human osteoblastic differentiation, another direction of cell differentiation [293]. It was found that induction of HO-1was associated with reduction of C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36, Wnt5b expression and the increase of β-catenin, pGSK3β, Wnt10b, Pref-1, shh, and adiponectin [280,283,[294][295][296], indicating that those key factors were responsible for HO-exerted effect on adipogenesis.…”

Featured Article: Induction of heme oxygenase with hemin improves pericardial adipocyte morphology and function in obese Zucker rats by enhancing proteins of regeneration

“…Importantly, these attributes of hemin were accompanied by the restoration of adipocyte morphology and improved adipocyte function as evidenced by increased adiponectin levels. Given that hypertriglyceridemia, hypercholesteromia, and excessive pericardial adiposity are major pathophysiological causes of heart failure and related cardiac complications, 8,[43][44][45][46] the suppression of hypertriglyceridemia, hypercholesteromia, and pericardial adiposity in hemin-treated ZFs, and the corresponding decline of adipocyte hypertrophy, TGF-b, osteopontin, pro-inflammatory macrophage M1 phenotype, TNF-a, IL-6, IL-1b, and 8-isoprostane, [22][23][24][25][26][27][28][29][30][31]54,[60][61][62][63] which were associated with the potentiation of the anti-inflammatory macrophage M2 phenotype, proteins of regeneration such as beta-catenin, Oct3/4, and pax2 [32][33][34] are among the multifaceted mechanisms by which the HO system restores adipocyte morphology and improved adipocyte function. Moreover, the effect of the HO system on the expression of proteins of regeneration such as Oct3/4 and pax2 is a novel mechanism unveiled by this study through which hemin may restore adipocyte morphology and function.…”

“…To investigate the mechanisms by which hemin improves pericardial adipocyte morphology, we measured the expression of proteins of regeneration such as beta-catenin, Oct3/4, and pax2 [32][33][34] in the adipose tissue. Our results indicate that the expressions of beta-catenin, Oct3/4, and pax2 in ZFs were significantly reduced as compared to the ZL control (Figure 7(a) to (c)).…”

“…1,8,9 Since osteopontin is known to promote inflammation, extracellular matrix invasion, and hypertrophy, [22][23][24][25][26][27][28][29][30][31] the effects of an upregulated HO system on the expression of osteopontin in pericardial adipocyte were assessed. Furthermore, we also investigated whether treatment with hemin improves pericardial adipocyte morphology and function by abating hypertrophy, oxidative stress, and inflammation, while concomitantly enhancing proteins of regeneration such as betacatenin, Oct3/4, and pax2 [32][33][34] in the adipose tissue. Moreover, the effects of the HO system on the expression of Oct3/4 and pax2 and osteopontin in pericardial adipose tissue have not been reported.…”

Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet

“…It is not surprising because oxidative related process such as oxidative stress is associated with adiposity caused by VAT accumulation [42,43]. In fact, as two important oxidant genes of oxidative stress, the expression levels of p47phox and GP91-PHOX were shown to be positively associated with VAT mass in mice or rats [43,44], suggesting VAT changes resulted in oxidative stress by regulating the expression of p47phox and GP91-PHOX. For antioxidant markers, oxidative stress reduced the levels of GPX3 in the plasma of obese subjects and adipose tissue of HFD mice [45,46] as well as GSTA4 expression in adipose tissue of obese C57BL/6J mice [47].…”