Vissarion Efthymiou, Adhideb Ghosh, Sean D. Kodani, Habib Muallem, Xavier Caubit, Waqar Ali, Lindsay Poulos, Henrique Camara, Anushka Gupta, Yasmine Belaïdouni, Sina A. Booeshaghi, Shiyi Yang, Ruchir Rastogi, Farnaz Shamsi, Ashley H. Vernon, Laurent Fasano, Assaf Rudich, Aaron Streets, Yu‐Hua Tseng, Mary‐Elizabeth Patti
Abstract 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 revealed 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 was identified as a candidate regulator of ADIPOMAT lo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibited differentiation, with downregulation of early adipogenic regulators (e.g. CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduced 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.