Recent studies have shown that heterogeneity among adipocytes exists within a single WAT depot. Our lab has uncovered three developmentally distinct subpopulations of WAT adipocytes distinguished by the expression of these genes: Wilms’ Tumor 1 (Wt1) (Type 1), Transgelin (Tagln) (Type 2), and Myxovirus 1 (Mx1) (Type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis showed that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo, and differentially contribute to the adipose tissue depots. This study extends these findings to investigate the role of Type 2 adipocytes during obesity. The number of Type 2 preadipocytes and adipocytes was not significantly altered by high fat diet induced obesity. However, greater than 80% of recruited macrophages, organized into crown-like structures were found in direct contact with Type 2 adipocytes, suggesting increased apoptosis of this adipocyte subpopulation. Furthermore, treatment of Type 2 adipocytes with the inflammatory cytokine TNFα promoted a 15% increase apoptosis specifically in Type 2 adipocytes, with no effects on other adipocytes. RNA-seq analysis of Type 2 adipocytes revealed a global downregulation of 102 of 298 known PPARγ regulated genes in Type 2 adipocytes. Although PPARγ mRNA was not altered, the protein level of PPARγ was reduced by 60% in Type 2 vs. control adipocytes. Pre-treatment of Type 2 adipocytes with the PPARγ agonist, rosiglitazone reduces TNFα-induced apoptosis in this subpopulation to similar levels found in control adipocytes, suggesting that reduced PPARγ activity in Type 2 adipocytes may, at least in part, regulates obesity-associated inflammation. Thus, further investigation of the physiological role of these adipocyte subpopulations are promising avenues of study to develop novel treatment strategies to combat diabetes and other disorders associated with the obesity epidemic.
J. Huang: None. R. Sharma: None. K.Y. Lee: None.