HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition

EMBO J. 2012 May 2;31(9):2103-16. doi: 10.1038/emboj.2012.71. Epub 2012 Mar 23.


The function of metabolic state in stemness is poorly understood. Mouse embryonic stem cells (ESC) and epiblast stem cells (EpiSC) are at distinct pluripotent states representing the inner cell mass (ICM) and epiblast embryos. Human embryonic stem cells (hESC) are similar to EpiSC stage. We now show a dramatic metabolic difference between these two stages. EpiSC/hESC are highly glycolytic, while ESC are bivalent in their energy production, dynamically switching from glycolysis to mitochondrial respiration on demand. Despite having a more developed and expanding mitochondrial content, EpiSC/hESC have low mitochondrial respiratory capacity due to low cytochrome c oxidase (COX) expression. Similarly, in vivo epiblasts suppress COX levels. These data reveal EpiSC/hESC functional similarity to the glycolytic phenotype in cancer (Warburg effect). We further show that hypoxia-inducible factor 1α (HIF1α) is sufficient to drive ESC to a glycolytic Activin/Nodal-dependent EpiSC-like stage. This metabolic switch during early stem-cell development may be deterministic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activins / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • DNA, Mitochondrial / analysis
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / physiology*
  • Female
  • Glycolysis*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Prostaglandin-Endoperoxide Synthases / metabolism


  • DNA, Mitochondrial
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Activins
  • Adenosine Triphosphate
  • Prostaglandin-Endoperoxide Synthases