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Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma).

ABSTRACT: One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-? (PPAR?). Here, we report that a deficiency of ?-arrestin-1 expression affects PPAR?-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that ?-arrestin-1 interacts with PPAR?. ?-Arrestin-1 suppressed the formation of a complex between PPAR? and 9-cis-retinoic acid receptor-? through its direct interaction with PPAR?. The interaction of ?-arrestin-1 with PPAR? repressed PPAR?/9-cis-retinoic acid receptor-? function but promoted PPAR?/nuclear receptor corepressor function in PPAR?-mediated adipogenesis and inflammatory gene expression. Consistent with these results, a deficiency of ?-arrestin-1 binding to PPAR? abolished its suppression of PPAR?-dependent adipogenesis and inflammatory responses. These results indicate that the regulation of PPAR? by ?-arrestin-1 is critical. Furthermore, in vivo expression of ?-arrestin-1 (but not the binding-deficient mutant) significantly repressed adipogenesis, macrophage infiltration, and diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Therefore, our findings not only reveal a molecular mechanism for the modulation of obesity by ?-arrestin-1 but also suggest a potential tactical approach against obesity and its associated metabolic disorders.

SUBMITTER: Zhuang LN

PROVIDER: S-EPMC3151083 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other

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Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma).

Zhuang Le-nan LN Hu Wen-xiang WX Xin Shun-mei SM Zhao Jian J Pei Gang G

The Journal of biological chemistry 20110623 32

One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-γ (PPARγ). Here, we report that a deficiency of β-arrestin-1 expression affects PPARγ-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that β-arrestin-1 interacts with PPARγ. β-Arrestin-1 suppressed the formation of a complex between PPARγ and 9-cis-retinoic acid receptor-α through its direct interaction with PPARγ. The intera ...[more]

PMID: 21700709

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma).

Publications

Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma).

Similar Datasets

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