Endocrine Abstracts

JOINT275

Androgen excess is a common endocrine disorder in women and drives a selective expansion of visceral adipose tissue (VAT). Mesothelial cell is only present in visceral but not subcutaneous adipose tissues. But its function is poorly understood. Single cell RNA sequencing (scRNA-seq) reveals a dramatic decrease in VAT mesothelial cell number upon androgen excess-induced obesity. This is in accompany of a malformation of extracellular matrix (ECM) in the VAT of female mice. Female mice with mesothelial cell-specific deletion of androgen receptor (Ar) are resistant to androgen excess-induced visceral obesity and ECM malformation. Depletion of mesothelial cells in VAT directly impairs ECM formation, accompanied by VAT gain and metabolic disorders even on a normal diet, highlighting the key function of mesothelial cells in VAT ECM formation. Furthermore, VAT organoids deficient of mesothelial cells exhibit compromised ECM formation and enhanced adipogenesis, which are reversed by mesothelial cell conditioned medium. Mechanistically, mesothelial cells abundantly secret proteoglycan Decorin (DCN), which is indispensable for ECM formation in VAT. Normalizing DCN expression in VAT rescues androgen excess-induced ECM malformation, visceral obesity and insulin resistance in female mice. These findings reveal the intermediatory function of mesothelial cell in aiding proper ECM formation and its implication in hyperandrogenism-induced visceral obesity.