Inhibition of PPAR gamma 2 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 PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) 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 PPAR gamma 2 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.
Yun
Zhong
Z
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Maecker
Heather L
HL
Johnson
Randall S
RS
Giaccia
Amato J
AJ
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D010100:Oxygen; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C491539:Bhlhe40 protein, mouse; C497443:Hif1a protein, mouse