Hypoxia-inducible factor-3alpha functions as an accelerator of 3T3-L1 adipose differentiation

Biol Pharm Bull. 2009 Jul;32(7):1166-72. doi: 10.1248/bpb.32.1166.


Hypoxia-inducible factor (HIF) is a heterodimer composed of HIF-alpha and -beta, and to date, three HIF-alpha subunits, HIF-1alpha, -2alpha, and -3alpha, have been identified. Among these HIF-alpha subunits, HIF-1alpha represses peroxisome proliferator activator gamma2 gene expression and then inhibits adipogenesis, and HIF-2alpha is induced during adipose differentiation and functions as a positive regulator of adipogenesis. We here found that like HIF-2alpha, HIF-3alpha was induced during 3T3-L1 adipose differentiation. Reporter gene analysis revealed that HIF-2alpha enhanced the promoter activity of the 5'-flanking region of the mouse HIF-3alpha gene (nucleotides -2710 to +56), while HIF-1alpha had no substantial effects on the promoter activity. These results suggested that HIF-2alpha, which was induced during adipogenesis, might regulate the HIF-3alpha gene expression. Furthermore, the 5'-deletion analysis revealed that the sequence between -251 and -228 in mouse HIF-3alpha promoter was essential in response to HIF-2alpha. We further examined the effect of ectopic expression of HIF-3alpha in 3T3-L1 cells on adipose differentiation and found that ectopic expression of HIF-3alpha at the early stage of differentiation induced the expression of several kinds of adipocytes-related genes and enhanced adipogenic potential. HIF-3alpha, which is induced by HIF-2alpha, might function as an accelerator of adipogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Adipogenesis / genetics
  • Adipogenesis / physiology*
  • Animals
  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Blotting, Western
  • Cell Differentiation*
  • Gene Expression Regulation
  • Mice
  • Promoter Regions, Genetic
  • Repressor Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Transcription Factors / physiology


  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Hif3a protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • endothelial PAS domain-containing protein 1