Multi-omics profiling reveals molecular features of visceral adiposity in autonomous cortisol secretion.

Autonomous cortisol secretion (ACS) from adrenal adenomas increases cardiometabolic risk. Visceral adiposity is a hallmark of ACS. We characterized ACS-associated visceral adiposity using multi-omics profiling of periadrenal adipose tissue and plasma. ACS exhibited higher visceral-to-subcutaneous fat ratio (VSR), adipocyte hypertrophy, and inflammation-related pathway enrichment than non-functioning adrenal tumors. RNA-seq deconvolution and immunohistochemistry indicated increased macrophage infiltration. Plasma steroid metabolomics identified 11-deoxycorticosterone (11-DOC), a mineralocorticoid metabolite, as positively associated with VSR in premenopausal ACS women independent of cortisol. The 11-DOC-associated gene module correlated with inflammation-related pathways, notably macrophage activation. Lipidomics identified ceramides as ACS discriminators, with Cer(d18:1/16:0) most strongly associated with inflammation- and lipid metabolism-related pathways. Mendelian randomization showed genetically predicted plasma Cer(d18:1/16:0) was positively associated with trunk fat mass. These findings identify circulating 11-DOC and adipose ceramide accumulation as molecular features associated with adipose inflammation and visceral adiposity in ACS, providing hypothesis-generating insights that require functional validation.