Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.
Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.
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发表时间：
2005
期刊：
影响因子：
7.7
通讯作者：
A. Tsuchida;T. Yamauchi;Sato Takekawa;Y. Hada;Yusuke Ito;Toshiyuki Maki;T. Kadowaki
中科院分区：
文献类型：
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作者：
A. Tsuchida;T. Yamauchi;Sato Takekawa;Y. Hada;Yusuke Ito;Toshiyuki Maki;T. Kadowaki
我们研究了过氧化物酶体增殖物激活受体（PPARalpha）、PPARgamma以及两者联合激活对肥胖糖尿病KKAy小鼠的影响，并研究了它们改善胰岛素敏感性的机制。通过其激动剂Wy-14，643激活PPARalpha，以及通过其激动剂罗格列酮激活PPARgamma，显著改善胰岛素敏感性。有趣的是，Wy-14，643和罗格列酮的组合对PPARalpha和-γ的双重激活显示出增加的功效。Wy-14，643处理的KKAy小鼠中的脂肪细胞大小远小于溶剂或罗格列酮处理的小鼠，表明PPARalpha的活化可防止脂肪细胞肥大。此外，Wy-14，643治疗减少炎症和白色脂肪组织（WAT）中巨噬细胞特异性基因的表达。重要的是，Wy-14，643治疗上调WAT中脂联素受体（AdipoR）-1和AdipoR 2的表达，而与非糖尿病对照小鼠相比，KKAy小鼠的WAT中脂联素受体（AdipoR）-1和AdipoR 2的表达有所降低。此外，Wy-14，643直接增加脂肪细胞和巨噬细胞中AdipoRs的表达并降低单核细胞趋化蛋白-1的表达。罗格列酮增加血清脂联素浓度和脂联素高分子量多聚体占总脂联素的比例。罗格列酮和Wy-14，643的组合增加WAT中的血清脂联素浓度和AdipoR表达。这些数据表明，PPARalpha活化可预防WAT中的炎症，PPARalpha和-γ的双重活化可通过增加脂联素和AdipoRs来增强脂联素的作用，从而改善肥胖诱导的胰岛素抵抗。
We examined the effects of activation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPARalpha activation by its agonist, Wy-14,643, as well as PPARgamma activation by its agonist, rosiglitazone, markedly improved insulin sensitivity. Interestingly, dual activation of PPARalpha and -gamma by a combination of Wy-14,643 and rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643-treated KKAy mice was much smaller than that of vehicle- or rosiglitazone-treated mice, suggesting that activation of PPARalpha prevents adipocyte hypertrophy. Moreover, Wy-14,643 treatment reduced inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly, Wy-14,643 treatment upregulated expression of the adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore, Wy-14,643 directly increased expression of AdipoRs and decreased monocyte chemoattractant protein-1 expression in adipocytes and macrophages. Rosiglitazone increased serum adiponectin concentrations and the ratio of high molecular weight multimers of adiponectin to total adiponectin. A combination of rosiglitazone and Wy-14,643 increased both serum adiponectin concentrations and AdipoR expression in WAT. These data suggest that PPARalpha activation prevents inflammation in WAT and that dual activation of PPARalpha and -gamma enhances the action of adiponectin by increasing both adiponectin and AdipoRs, which can result in the amelioration of obesity-induced insulin resistance.