Siah2 Expression in Adipocyte Progenitor Cells

Abstract

Obesity-related insulin resistance is associated with adipose tissue inflammation and visceral adipose tissue expansion via adipocyte hypertrophy and impaired recruitment of new progenitor cells to undergo adipogenesis (hyperplasia). Deletion of the ubiquitin ligase Seven-in-absentia homolog 2 (Siah2) in obese mice significantly reduced adipose tissue inflammation and insulin resistance compared to obese wild type mice. However, larger adipocyte size accompanied this phenotype and subsequent experiments with adipose tissue stromal vascular fraction (SVF) cells showed adipogenesis required Siah2. In an earlier study, we found Siah2 affects adipogenesis by enhancing gene expression of the PPARγ coactivator, Zfp423 via proteasome-dependent degradation of ZFP521, a transcriptional repressor of Zfp423. ZFP423 is an early marker of preadipocyte determination that is expressed in adipocyte progenitor cells. Although Siah2 mediates adipogenesis and is highly expressed in the adipose tissue stromal vascular cell fraction, cell-specific expression of Siah2 in adipose tissue is not well characterized. We found that Siah2 is highly expressed in macrophage. RNA-seq and microarray data from the Immunological Genome Project (Immgen.org) also reported Siah2 expression in lymphocytes. To identify Siah2 expression profile in adipose tissue, unsorted cells and magnetically sorted macrophage, T-cell, B-cell, and SCA-1 positive progenitor cells from mouse adipose tissues SVF were analyzed for Siah2 expression. In parallel, in situ hybridization RNAscope of fat pads was employed to inspect Siah2 mRNA localization in adipose tissue. Since our evidence indicates Siah2 acts upstream of ZFP423, we predict Siah2 is expressed in adipocyte progenitor cells as well as immune cells in adipose tissue. This work will provide the groundwork to better understand how Siah2 controls commitment of progenitor cells to the adipocyte lineage and links obesity to adipose tissue inflammation and insulin resistance. Disclosure T. Dang: None. G.E. Kilroy: None. J.L. Taylor: None. Y. Yu: None. E. Floyd: None.