Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis

Nat Metab. 2024 May;6(5):825-836. doi: 10.1038/s42255-024-01029-4. Epub 2024 Apr 15.


Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.

MeSH terms

  • Animals
  • Gluconeogenesis* / genetics
  • Hepatocytes / metabolism
  • Histone Deacetylases* / genetics
  • Histone Deacetylases* / metabolism
  • Liver* / metabolism
  • Mice
  • Mice, Knockout*
  • Nuclear Receptor Co-Repressor 1* / genetics
  • Nuclear Receptor Co-Repressor 1* / metabolism
  • Nuclear Receptor Co-Repressor 2* / genetics
  • Nuclear Receptor Co-Repressor 2* / metabolism
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism
  • Receptors, Glucocorticoid* / genetics
  • Receptors, Glucocorticoid* / metabolism


  • Receptors, Glucocorticoid
  • Nuclear Receptor Co-Repressor 1
  • histone deacetylase 3
  • Histone Deacetylases
  • Nuclear Receptor Co-Repressor 2
  • Ncor1 protein, mouse
  • Nuclear Receptor Coactivator 2
  • Ncor2 protein, mouse