Open AccessPerivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity
Author(s) -
Bo Shan,
Mengle Shao,
Qianbin Zhang,
Chelsea Hepler,
Vivian A. Paschoal,
Spencer Barnes,
Lavanya Vishvanath,
Yu An,
Jen–Der Lin,
Venkat S. Malladi,
Douglas W. Strand,
Olga T. Gupta,
Joel K. Elmquist,
Dayoung Oh,
Rana K. Gupta
Publication year - 2020
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-020-00301-7
Subject(s) - adipose tissue , proinflammatory cytokine , inflammation , adipose tissue macrophages , white adipose tissue , endocrinology , downregulation and upregulation , macrophage , medicine , biology , mesenchymal stem cell , cancer research , microbiology and biotechnology , biochemistry , gene , in vitro
Chronic low-grade white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a subpopulation of mouse WAT perivascular (PDGFRβ + ) cells, termed fibro-inflammatory progenitors (FIPs), activate proinflammatory signalling cascades shortly after the onset of high-fat diet feeding and regulate proinflammatory macrophage accumulation in WAT in a TLR4-dependent manner. FIPs activation in obesity is mediated by the downregulation of zinc-finger protein 423 (ZFP423), identified here as a transcriptional corepressor of NF-κB. ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NF-κB by inducing a p300-to-NuRD coregulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRβ + cells suppresses inflammatory signalling in FIPs and attenuates metabolic inflammation of visceral WAT in obesity. Inducible inactivation of Zfp423 in PDGFRβ + cells increases FIP activity, exacerbates adipose macrophage accrual and promotes WAT dysfunction. These studies implicate perivascular mesenchymal cells as important regulators of chronic adipose-tissue inflammation in obesity and identify ZFP423 as a transcriptional break on NF-κB signalling.