SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation

Cell Metab. 2016 Sep 13;24(3):474-484. doi: 10.1016/j.cmet.2016.07.025. Epub 2016 Aug 25.


Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2 dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid-dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP, and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice, both systems of elevated SREBP-1c-driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition of SREBP processing. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions.

Keywords: SETDB2; SREBP; fasting liver; glucocorticoid receptor; insig2.

Publication types

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

MeSH terms

  • Animals
  • Chromatin / metabolism
  • Dexamethasone / pharmacology
  • Enhancer Elements, Genetic / genetics
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Genetic Loci
  • Glucocorticoids / pharmacology*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Lipid Metabolism / drug effects*
  • Liver / drug effects
  • Liver / metabolism
  • Lysine / metabolism
  • Male
  • Membrane Proteins / metabolism*
  • Methylation / drug effects
  • Mice, Inbred C57BL
  • Mice, Obese
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Transcription, Genetic / drug effects


  • Chromatin
  • Glucocorticoids
  • Histones
  • Insig2 protein, mouse
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Sterol Regulatory Element Binding Protein 1
  • Dexamethasone
  • Histone-Lysine N-Methyltransferase
  • Lysine