Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity.

Nature metabolism 2020 Nov

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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.

Citation

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. Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity. Nature metabolism. 2020 Nov;2(11):1332-1349