NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism

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.

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Figure 1: Induction of NR4A receptor expression in liver in response to the glucagon-cAMP axis and fasting.
Figure 2: Complementary regulation of glucose metabolism by Nur77 and PGC-1α in primary hepatocytes.
Figure 3: NR4A proteins are direct regulators of genes involved in glucose metabolism.
Figure 4: Activation of gluconeogenesis by Nur77 in vivo.
Figure 5: Inhibition of NR4A receptor activity lowers blood glucose in physiology and diabetes.

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Acknowledgements

We thank O. Conneely and S. Mullican for discussions and for sharing unpublished data. We are grateful to B. Spiegelman for PGC-1α adenovirus; M. Montminy for A-CREB, PGC-1α RNAi and control scrambled RNAi adenovirus; S. Tetradis for Nur77 and Nurr1 adenovirus; and T. Perlmann for Nurr1 adenovirus. We thank L. Wu, M. Johnson and the UCLA viral vector core (N. Kasahara, D. Cohen and E. Faure, funded by US National Institutes of Health (NIH) grant P30 DK041301) for help with adenovirus experiments. We also thank E. Saez, L. Chao, S. Beaven, A. Castrillo, M. Chen, Y. Zhang, and S. Zhang for their input. P.T is an Investigator of the Howard Hughes Medical Institute. This work was supported by grants from the NIH (HL30568 to P.T. and DK58132 to I.J.K.) and a Bristol-Myers Squibb Freedom to Discover Award.

Author information

L.P. designed and performed experiments and wrote the manuscript. H.W. and B.V. designed and performed experiments. D.C.W. performed experiments. I.J.K. designed experiments, performed data analysis and edited the manuscript. P.T. designed experiments and wrote the manuscript.

Correspondence to Peter Tontonoz.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Induction of NR4A expression by the cAMP axis requires CREB family proteins but not PGC-1α. (PDF 289 kb)

Supplementary Fig. 2

Regulation of gene expression by Nur77 does not require PGC-1α. (PDF 247 kb)

Supplementary Fig. 3

Sequences and locations of putative NBREs in promoters of gluconeogenic genes. (PDF 302 kb)

Supplementary Fig. 4

Effects of Nur77 expression on key genes involved in control of glucose metabolism. (PDF 175 kb)

Supplementary Fig. 5

A mutant Nur77 receptor antagonizes NR4A action on target promoters. (PDF 212 kb)

Supplementary Table 1

Real-time PCR (SyberGreen) primers used. (PDF 15 kb)

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