Gender Specific Effects of Nr4a1 in Obese Mice

Abstract

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. While high fat fed male βNr4a1−/− have improved fasting and non-fasting blood glucose levels and no change in glucose tolerance, high fat fed female βNr4a1−/− mice have impaired glucose tolerance as early as one month after beginning high fat feeding. We also found that βNr4a1−/− female mice have decreased β-cell mass and decreased expression in known targets of Nr4a1 regulation including Eno1 and SDHβ. Our data suggest that Nr4a1 is critical for maintenance of beta cell function, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function. NIH R15DK124835-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.