Homeostatic levels of SRC-2 and SRC-3 promote early human adipogenesis

J Cell Biol. 2011 Jan 10;192(1):55-67. doi: 10.1083/jcb.201004026.


The related coactivators SRC-2 and SRC-3 interact with peroxisome proliferator activated receptor γ (PPARγ) to coordinate transcriptional circuits to promote adipogenesis. To identify potential coactivator redundancy during human adipogenesis at single cell resolution, we used high content analysis to quantify links between PPARγ, SRC-2, SRC-3, and lipogenesis. Because we detected robust increases and significant cell-cell heterogeneity in PPARγ and lipogenesis, without changes in SRC-2 or SRC-3, we hypothesized that permissive coregulator levels comprise a necessary adipogenic equilibrium. We probed this equilibrium by down-regulating SRC-2 and SRC-3 while simultaneously quantifying PPARγ. Individual or joint knockdown equally inhibits lipid accumulation by preventing lipogenic gene engagement, without affecting PPARγ protein levels. Supporting dominant, pro-adipogenic roles for SRC-2 and SRC-3, SRC-1 knockdown does not affect adipogenesis. SRC-2 and SRC-3 knockdown increases the proportion of cells in a PPARγ(hi)/lipid(lo) state while increasing phospho-PPARγ-S114, an inhibitor of PPARγ transcriptional activity and adipogenesis. Together, we demonstrate that SRC-2 and SRC-3 concomitantly promote human adipocyte differentiation by attenuating phospho-PPARγ-S114 and modulating PPARγ cellular heterogeneity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Adipogenesis* / genetics
  • Cell Differentiation / genetics
  • Female
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • HeLa Cells
  • Homeostasis* / genetics
  • Humans
  • Imaging, Three-Dimensional
  • Lipogenesis / genetics
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Nuclear Receptor Coactivator 3 / genetics
  • Nuclear Receptor Coactivator 3 / metabolism*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phenotype
  • Phosphorylation
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Reproducibility of Results


  • NCOA2 protein, human
  • Nuclear Receptor Coactivator 2
  • PPAR gamma
  • RNA, Messenger
  • RNA, Small Interfering
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3