GSE134868
Mural Cell ZFP423 Controls Adipose Tissue Macrophage Accrual in Obesity [ChIP-seq]
Chronic low-grade visceral white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a specific subpopulation of adipose tissue perivascular (PDGFRb+) stromal cells, termed “fibro-inflammatory progenitors” (FIPs), activate  pro-inflammatory signaling cascades shortly after the onset of high-fat diet feeding of mice and control the accumulation of pro-inflammatory macrophages in WAT. The activation of FIPs is mediated by the downregulation of ZFP423, identified here as a transcriptional co-regulator of  NFkB. Biochemical analysis of ZFP423-protein complexes and ChIP-seq analysis reveal that  ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NFkB by inducing  a co-regulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRb+ cells  suppresses inflammatory signaling in FIPs and attenuates macrophage accumulation within  visceral WAT of obese mice. Conversely, inducible inactivation of Zfp423 in PDGFRb+ cells increases FIP activity, exacerbates adipose macrophage accrual, and promotes WAT  dysfunction in obese mice. These studies implicate mural cells as sentinels and gatekeepers of adipose tissue inflammation in obesity. Overall design: We performed NFKB p65 subunit binding sites (using ChIP-seq) of FIPs (pooled samples, ~5,000,000 cells per genotype) isolated from both control and Mural-Zfp423TG mice after 2 hours of  LPS (100ng/mL) treatment.