P-367 - PPARγ phosphorylation at Ser186 regulates metabolic inflammation via modulating redox balance in adipocyte tissue macrophages

Abstract

Obesity is a chronic inflammation in which inflammatory adipocyte tissue macrophages (ATMs) are regarded as prominent players. Our previous works have suggested that PPARg, a master regulator of adipogenesis, modulates macrophage differentiation and polarization, whereby impacts metabolic inflammation. Given that PPARg activities are fine-tuned by its post-translational modifications, we have been trying to identify the new modification sites of PPARg in adipose tissue macrophages. We isolated ATMs and analyzed PPARg phosphorylation with phosphoproteomics and other related techniques. The results demonstrate that PPARg phosphorylation in ATMs was gradually increased along with the obesity progression, which induced the progressive metabolic inflammation. It was noteworthy that PPARg 186 phosphorylation was found to modulate GSH/GSSG ratio in ATMs, which resulted in modified fatty acid metabolic pathway, dysregulated mitochondrial homeostasis, and ultimately aggressive inflammatory responses, especially TNFa expression. By combined using chemical screen system and bioactivity analysis, we found that small molecule SWX12 could block PPARg phosphorylation and then regulate intracellular redox balance in ATMs, which was proven to be related with local inflammation reduction.