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    Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77

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    Author
    Chao, LC; Wroblewski, K; Zhang, Z; Pei, L; Vergnes, L; Ilkayeva, OR; Ding, SY; Reue, K; Watt, MJ; Newgard, CB; ...
    Date
    2009-12-01
    Source Title
    Diabetes
    Publisher
    AMER DIABETES ASSOC
    University of Melbourne Author/s
    Watt, Matthew
    Affiliation
    Physiology
    Metadata
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    Document Type
    Conference Paper
    Citations
    Chao, L. C., Wroblewski, K., Zhang, Z., Pei, L., Vergnes, L., Ilkayeva, O. R., Ding, S. Y., Reue, K., Watt, M. J., Newgard, C. B., Pilch, P. F., Hevener, A. L. & Tontonoz, P. (2009). Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77. DIABETES, 58, (12), pp.2788-2796. AMER DIABETES ASSOC. https://doi.org/10.2337/db09-0763.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/254713
    DOI
    10.2337/db09-0763
    Abstract
    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. RESEARCH DESIGN AND 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.

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