NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism.
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.
Pei
Liming
L
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.
Waki
Hironori
H
Vaitheesvaran
Bhavapriya
B
Wilpitz
Damien C
DC
Kurland
Irwin J
IJ
Tontonoz
Peter
P
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D005934:Glucagon / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015124:8-Bromo Cyclic Adenosine Monophosphate; D005934:Glucagon; D005947:Glucose