We have shown that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for beta cell mitochondrial respiration and fuel utilization, and that loss of either factor impedes fuel utilization and insulin secretion. We have also demonstrated that prolonged culture of INS-1 832/13 beta cells with progressively increasing concentrations of palmitic acid results in decreased Nr4a1 and Nr4a3 expression, impaired mitochondrial respiration, and reduced insulin secretion. Here we explore the effect of 20-week high fat diet on wild type mice and mice deficient for either Nr4a1 or Nr4a3. Nr4a1 and Nr4a3 knock out mice have greater body weight than wild type animals when on a high fat diet. Mice deficient for Nr4a1 or Nr4a3 have no significant change in non-fasting blood glucose measurements as compared to wild type under normal chow conditions. Non-fasting blood glucose was elevated in both Nr4a1 and Nr4a3 knock out mice under high fat feeding conditions. Fasting glucose tolerance tests also demonstrate that Nr4a1 and Nr4a3 knock out mice have impaired glucose tolerance as compared to wild type animals under high fat feeding. Mitochondrial respiration of muscle, liver, adipose and islets are impaired as compared to wild type controls under high fat feeding. Glucose stimulated insulin secretion is impaired in islets from Nr4a1 or Nr4a3 knock out mice fed a high fat diet. These data demonstrate changes in various metabolic tissues as a result of high fat feeding and deletion of the Nr4a orphan nuclear receptors, demonstrating that they play a critical role in systemic fuel utilization.
C.J. Smith: None. K.B. Kener: None. J.S. Tessem: None.