Single-nucleus analysis of human white adipose tissue reveals adipocyte subsets with distinct metabolic profiles

Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis reveals 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAT^hi vs. ADIPOMAT^lo). ADIPOMAT^lo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMAT^lo were more abundant in higher BMI donors, while SAT-resident ADIPOMAT^lo associated with impaired glycemia. TSHZ3 is identified as a candidate regulator of ADIPOMAT^lo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibits differentiation, with downregulation of early adipogenic regulators (e.g., CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduces SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.