Inhibition of PPARγ2 gene expression by the HIF-1-regulated gene DEC1/Stra13:: A mechanism for regulation of adipogenesis by hypoxia

Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O-2) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPARgamma2 nuclear hormone receptor transcription, and overexpression of PPARgamma2 or C/EBPbeta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1alpha (HIF-1alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPARgamma2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O-2-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O-2 sensing may be used to inhibit adipogenesis and control obesity.