Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity

Area of Science:

• Cell Biology
• Metabolic Syndrome Research
• Immunology

Background:

• Chronic low-grade inflammation in white adipose tissue (WAT) is a key feature of obesity and metabolic syndrome.
• Perivascular cells in WAT play a role in metabolic inflammation.

Purpose of the Study:

• To investigate the role of perivascular cells in WAT inflammation during obesity.
• To identify molecular mechanisms regulating fibro-inflammatory progenitor (FIP) activation in obesity.
• To explore the function of zinc-finger protein 423 (ZFP423) in metabolic inflammation.

Main Methods:

• Utilized mouse models with high-fat diet feeding.
• Investigated subpopulations of WAT perivascular (PDGFRβ+) cells, termed FIPs.
• Analyzed the role of ZFP423 as a transcriptional corepressor of NF-κB.
• Employed doxycycline-inducible expression systems to manipulate ZFP423 levels in PDGFRβ+ cells.

Main Results:

• FIPs activate proinflammatory signaling and promote macrophage accumulation in WAT in a TLR4-dependent manner.
• ZFP423 downregulation mediates FIP activation in obesity by enabling NF-κB p65 subunit activity.
• ZFP423 suppresses NF-κB by inducing a p300-to-NuRD coregulator switch.
• Inducible ZFP423 expression in FIPs attenuates WAT inflammation, while its inactivation exacerbates it.

Conclusions:

• Perivascular mesenchymal cells are critical regulators of adipose tissue inflammation in obesity.
• ZFP423 acts as a crucial transcriptional brake on NF-κB signaling, controlling FIP activity and metabolic inflammation.