Abstract
Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. Previous studies demonstrated the beneficial effects of epoxyeicosatrienoic acids (EETs) on metabolic disorders and inflammation. Here we investigated the effects of CYP2J2-EETs-sEH metabolic pathway on insulin resistance in mice and the potential mechanisms. High fat diet (HFD)-induced obesity caused metabolic dysfunction with more weight gain, elevated glucose and lipids levels, impaired glucose tolerance and insulin sensitivity, while increase in EETs level by rAAV-mediated CYP2J2 overexpression, administration of sEH inhibit TUPS or EETs infusion significantly attenuated these metabolic disorders. EETs inhibited macrophages recruitment to adipose tissue and their switch to classically activated macrophage (M1) phenotype, while preserved the alternatively activated macrophage (M2) phenotype, which was accompanied by substantially reduced adipose tissue and systemic inflammation and insulin resistance. In vitro studies further clarified the effects of EETs on macrophage infiltration and polarization, and microarray assays showed that cAMP-EPAC signaling pathway was involved in these processes. Collectively, these results described key beneficial immune-regulatory properties and metabolic regulation of CYP2J2-EETs-sEH metabolic pathway, and indicated therapeutic potential of EETs in obesity-induced insulin resistance and related inflammatory diseases through modulating macrophage polarization targeting cAMP-EPAC signaling pathway.
Highlights
Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases
We found that 11,12-epoxyeicosatrienoic acids (EETs) level in High fat diet (HFD)-induced mice was lower than that in mice treated with normal diet (ND). 11,12-EET/dihydroxyeicosatrienoic acids (DHETs) in serum and urine were calculated as the soluble epoxide hydrolase (sEH) activity (Figure e,f), results showed that sEH inhibitor obviously inhibit sEH activity, while HFD had no effect
These results demonstrated that overexpression of CYP2J2 and inhibition of sEH activity by TUPS increased EETs level in vivo
Summary
Polarization in Adipose Tissue received: 13 December 2016 accepted: 27 March 2017. Published: 25 April 2017 Meiyan Dai, Lujin Wu, Peihua Wang, Zheng Wen, Xizhen Xu & Dao Wen Wang. Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. In vitro studies further clarified the effects of EETs on macrophage infiltration and polarization, and microarray assays showed that cAMP-EPAC signaling pathway was involved in these processes These results described key beneficial immune-regulatory properties and metabolic regulation of CYP2J2-EETs-sEH metabolic pathway, and indicated therapeutic potential of EETs in obesity-induced insulin resistance and related inflammatory diseases through modulating macrophage polarization targeting cAMP-EPAC signaling pathway. We hypothesize that EETs regulate adipose tissue macrophages polarization and prevent HFD-induced insulin resistance in mice. The increase in EETs levels by overexpression of CYP2J2 or administration of sEH inhibitor TUPS, or directly by infusion of EETs with osmic minipump in mice, was induced to explore the effects of EETs on adipose tissue macrophages polarization.
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