ISL1 regulates peroxisome proliferator-activated receptor γ activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.

While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells, we have identified evidence for the activity of 2,568 genes during the early phase of adipocyte differentiation. One of these, the ISL1 gene, was of interest since its expression was markedly upregulated 1 h after initiation of differentiation, with a subsequent rapid decline. Overexpression of ISL1 at early times during adipocyte differentiation but not at later times was found to profoundly inhibit differentiation. This was accompanied by moderate downregulation of peroxisome proliferator-activated receptor γ (PPARγ) levels, substantial downregulation of PPARγ downstream genes, and downregulation of bone morphogenetic protein 4 (BMP4) levels in preadipocytes. Readdition of BMP4 overcame the inhibitory effect of ISL1 on the expression of PPARγ but not aP2, a gene downstream of PPARγ, and BMP4 also partially rescued ISL1 inhibition of adipogenesis, an effect which is additive with rosiglitazone. These results suggest that ISL1 is intimately involved in early regulation of adipogenesis, modulating PPARγ expression and activity via BMP4-dependent and -independent mechanisms. Our time course gene expression survey sets the stage for further studies to explore other early and immediate regulators.