Combined pharmacological targeting of CD9⁺ progenitors alleviates obesity-induced adipose tissue fibrosis and metabolic impairment.

Abstract

Fibrosis in visceral white adipose tissue (vWAT) is closely associated with tissue dysfunction and systemic metabolic disturbances in obesity. Identifying pathways amenable to drug intervention to prevent fibrotic changes in vWAT is a critical step in addressing the array of metabolic complications associated with obesity. CD9⁺ adipose progenitors (Progs) are key drivers of vWAT fibrosis. Here, we explore pharmacological strategies to target these cells and improve metabolic health. Profiling of CD9⁺ Progs reveals pro-fibrotic pathways that can be targeted by the Food and Drug Administration (FDA)-approved drugs nintedanib and celecoxib. Treatment with this combination blocks the progression of vWAT fibrosis and improves systemic metabolism in obese mice. Within the CD9⁺ Prog population, both Ly-6C⁺ Progs and mesothelial cells adopt a pro-fibrotic phenotype during obesity, a shift markedly reduced by the drug treatment. Our data highlight the importance of targeting adipose progenitors to counteract fibrosis and preserve adipose tissue function.