Nature Medicine
- 12, 1048 - 1055 (2006)
Published online: 13 August 2006; | doi:10.1038/nm1471
NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolismLiming Pei1, Hironori Waki1, Bhavapriya Vaitheesvaran2, Damien C Wilpitz1, Irwin J Kurland2 & Peter Tontonoz11
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, 675 Charles E. Young Drive South, Los Angeles, California 90095, USA. 2
Departments of Medicine, Pharmacological Sciences, Physiology and Biophysics, State University of New York, HSC T15-067, Stony Brook, New York 11794, USA.
Correspondence should be addressed to Peter Tontonoz ptontonoz@mednet.ucla.edu 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.
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