A central aspect of type 2 diabetes disease progression is impaired functional β-cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the β-cell. Nr4a1 expression is decreased in the β-cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetics. Here we demonstrate sex specific effects of β-cell specific Nr4a1 deletion under high fat chow feeding. While female and male βNr4a1-/- mice were no different than wild type controls when fed a standard chow diet, a clear sex dependent difference is observed when fed a high fat diet. High fat fed male βNr4a1-/- have improved fasting and non-fasting blood glucose levels, high fat fed female βNr4a1-/- mice have impaired glucose tolerance as early as two months after beginning high fat feeding. Furthermore, female βNr4a1-/- mice have decreased β-cell mass and improved insulin tolerance. Given the sex specific differences in glucose tolerance, we demonstrated that female mice fed a high fat diet have increased circulating estrogen, and that treatment of INS-1 832/13 cells and primary mouse islets with estradiol resulted in increased expression of Nr4a1 and not the other two Nr4a family members. Our data suggest that Nr4a1 is critical for estrogen mediated maintenance of beta cell function and mass under obesogenic conditions, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function.
J.S.Tessem: None. J.Herring: None.
National Institutes of Health (1R15DK124835-01A1)