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.