NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism

Liming Pei, Hironori Waki, Bhavapriya Vaitheesvaran, Damien C. Wilpitz, Irwin J. Kurland, Peter Tontonoz

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

Hepatic glucose production is crucial for glucose homeostasis, and its dysregulation contributes to the pathogenesis of diabetes. Here, we show that members of the NR4A family of ligand-independent orphan nuclear receptors are downstream mediators of cAMP action in the hormonal control of gluconeogenesis. Hepatic expression of Nur77, Nurr1 and NOR1 is induced by the cAMP axis in response to glucagon and fasting in vivo and is increased in diabetic mice that exhibit elevated gluconeogenesis. Adenoviral expression of Nur77 induces genes involved in gluconeogenesis, stimulates glucose production both in vitro and in vivo, and raises blood glucose levels. Conversely, expression of an inhibitory mutant Nur77 receptor antagonizes gluconeogenic gene expression and lowers blood glucose levels in db/db mice. These results outline a previously unrecognized role for orphan nuclear receptors in the transcriptional control of glucose homeostasis.

Original languageEnglish (US)
Pages (from-to)1048-1055
Number of pages8
JournalNature Medicine
Volume12
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

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Orphan Nuclear Receptors
Metabolism
Gluconeogenesis
Glucose
Liver
Blood Glucose
Homeostasis
Medical problems
Glucagon
Gene expression
Fasting
Genes
Ligands
Gene Expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. / Pei, Liming; Waki, Hironori; Vaitheesvaran, Bhavapriya; Wilpitz, Damien C.; Kurland, Irwin J.; Tontonoz, Peter.

In: Nature Medicine, Vol. 12, No. 9, 09.2006, p. 1048-1055.

Research output: Contribution to journalArticle

Pei, L, Waki, H, Vaitheesvaran, B, Wilpitz, DC, Kurland, IJ & Tontonoz, P 2006, 'NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism', Nature Medicine, vol. 12, no. 9, pp. 1048-1055. https://doi.org/10.1038/nm1471
Pei, Liming ; Waki, Hironori ; Vaitheesvaran, Bhavapriya ; Wilpitz, Damien C. ; Kurland, Irwin J. ; Tontonoz, Peter. / NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. In: Nature Medicine. 2006 ; Vol. 12, No. 9. pp. 1048-1055.
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