Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity

Bo Shan, Mengle Shao, Qianbin Zhang, Chelsea Hepler, Vivian A. Paschoal, Spencer D. Barnes, Lavanya Vishvanath, Yu A. An, Lin Jia, Venkat S. Malladi, Douglas W. Strand, Olga T. Gupta, Joel K. Elmquist, Dayoung Oh, Rana K. Gupta

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1332-1349
Number of pages18
JournalNature Metabolism
Volume2
Issue number11
DOIs
StatePublished - Nov 2020

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology
  • Medicine(all)

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