Nr4a3 deficiency disrupts MEK1-ERK1/2-Drp1 signaling, driving adiposity and glucose intolerance in male mice.

Obesity is strongly associated with elevated blood glucose levels, glucose intolerance, insulin resistance, and type 2 diabetes. The Nr4a family of orphan nuclear receptors is essential for proliferation, cell survival, mitochondrial function, and fuel utilization in a tissue-dependent manner. Nr4a3 overexpression has been shown to decrease blood glucose levels and improve glucose tolerance. Here, we present the effects of full body Nr4a3 deletion in mice fed a standard chow diet. We demonstrate that male and female Nr4a3 knockout mice fed a standard chow diet have elevated nonfasting blood glucose and impaired glucose tolerance. Male Nr4a3 knockout mice have increased body weight, without changes in body length, food intake, movement, or energy expenditure. Interestingly, male, but not female, Nr4a3 knockout mice have increased weight of all adipose depots with increased adipocyte cell size. Furthermore, male Nr4a3 mice have impaired adipose mitochondrial respiration, with normal liver and soleus respiration. Finally, we show a significant decrease in Drp1 mRNA, Drp1 protein, and phosphorylated DRP1 levels. These data suggest that Nr4a3 loss impairs expression of the key mitochondrial fission gene Drp1, resulting in impaired adipose mitochondrial respiration and ultimately increasing adipocyte size, adipose depot mass, and body mass. These data demonstrate that Nr4a3 is critical for proper adipocyte function.NEW & NOTEWORTHY This study reveals that full-body Nr4a3 deletion in mice leads to elevated blood glucose, impaired glucose tolerance, and increased adiposity, particularly in males. Notably, male Nr4a3 knockout mice exhibited enlarged adipocytes and impaired mitochondrial respiration in adipose tissue, which is linked to reduced expression of the mitochondrial fission gene DRP1. These findings highlight Nr4a3's critical role in regulating glucose metabolism and adipose tissue function, with implications for understanding obesity and type 2 diabetes.