Pro-inflammatory Macrophages suppress PPAR gamma activity in Adipocytes via S-nitrosylation

分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-12

Yin, Ruiying Fang, Li Li, Yingjia Wang, Nanping Yin, Ruiying Fang, Li Li, Yingjia Wang, Nanping Xue, Peng Li, Yazi Chen, Chang Guan, Youfei Wang, Nanping Chang, Yongsheng Chang, Yongsheng

摘要： Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a ligand-activated nuclear receptor and plays an essential role in insulin signaling. Macrophage infiltration into adipose tissue is a character of metabolic inflammation and closely related to insulin resistance in type 2 diabetes. The mechanism by which pro-inflammatory macrophages cause insulin resistance remains to be elucidated. Here we showed that coculture with macrophages significantly suppressed the transcriptional activity of PPAR gamma on its target genes in 3T3-L1 preadipocytes and diabetic primary adipocytes, depending on inducible nitric oxide synthase (iNOS). We further showed that PPAR gamma underwent S-nitrosylation in response to nitrosative stress. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosylation at cysteine 168 was responsible for the impairment of PPAR gamma function. Extended exposure to NO instigated the proteasome-dependent degradation of PPAR gamma. Consistently, in vivo evidence revealed an association of the decreased PPAR gamma protein level with increased macrophage infiltration in visceral adipose tissue (VAT) of obese diabetic db/db mice. Together, our results demonstrated that pro-inflammatory macrophages suppressed PPAR gamma activity in adipocytes via S-nitrosylation, suggesting a novel mechanism linking metabolic inflammation with insulin resistance. (C) 2015 Elsevier Inc. All rights reserved.

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