Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77.
OBJECTIVE
Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metabolism in vivo, we challenged Nur77 null mice with high-fat feeding.


METHODS
Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 months. We determined glucose tolerance, tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression of glucose and lipid metabolism genes.


RESULTS
Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp studies revealed greater high-fat diet-induced insulin resistance in both skeletal muscle and liver of Nur77 null mice compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4 protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely reflecting the lipogenic effect of hyperinsulinemia.


CONCLUSIONS
Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metabolism and highlight the physiological contribution of muscle Nur77 to this regulatory pathway.
Chao
Lily C
LC
Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, California, USA.
Wroblewski
Kevin
K
Zhang
Zidong
Z
Pei
Liming
L
Vergnes
Laurent
L
Ilkayeva
Olga R
OR
Ding
Shi Ying
SY
Reue
Karen
K
Watt
Matthew J
MJ
Newgard
Christopher B
CB
Pilch
Paul F
PF
Hevener
Andrea L
AL
Tontonoz
Peter
P
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D012107:Research Design; D015398:Signal Transduction
D001786:Blood Glucose; D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D007328:Insulin; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C495693:Slc2a4 protein, mouse; D011972:Receptor, Insulin; D005947:Glucose