Reduced Expression of FOXC2 and Brown Adipogenic Genes in Human Subjects with Insulin Resistance

Abstract

We investigated subcutaneous adipose tissue expression of FOXC2 and selected genes involved in brown adipogenesis in adult human subjects in whom we have previously identified a reduced potential of precursor cell commitment to adipose-lineage differentiation in relation to insulin resistance. Gene expression was studied using quantitative real time polymerase chain reaction. The relation between the expression of brown adipogenic genes and the genes involved in progenitor cell commitment, adipose cell size, and insulin sensitivity in vivo was analyzed. The expression of FOXC2, MASK, MAP3K5, retinoblastoma protein (pRb), peroxisome proliferator-activated protein gamma (PPARgamma), and retinoid X receptor gamma (RXRgamma) was decreased in the insulin-resistant compared with insulin-sensitive subjects, whereas PPARgamma-2 and CCAAT/enhancer binding protein alpha (C/EBPalpha) showed no differential expression. The FOXC2 expression correlated with that of Notch and Wnt signaling genes, as well as of the genes studied participating in brown adipogenesis, including MASK, MAP3K5, PPARgamma, pRb, RXRgamma, and PGC-1. A second-level correlation between PPARgamma and UCP-1 was also significant. In addition, the expression of MASK, MAP3K5, pRb, RXRgamma, and PGC-1 inversely correlated with adipose cell mass and also correlated with the glucose disposal rate in vivo. Our results suggest that a reduced brown adipose phenotype is associated with insulin resistance and that a basal brown adipose phenotype may be important for maintaining normal insulin sensitivity.