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 journalArticlepeer-review

266 Scopus citations


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
Issue number9
StatePublished - Sep 2006
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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