2585-P: NR4A3 Is Vital for MEK1-ERK1/2-DRP1 Signaling in Adipocytes

Introduction and Objective: Obesity, characterized by excessive adiposity, is a major risk factor for type 2 diabetes (T2D). Nr4a3 (nuclear receptor subfamily 4 group A member 3) is a transcription factor that modulates mitogen-activated protein kinase (MAPK) signaling, particularly the ERK pathway, which regulates lipolysis, mitochondrial function, and respiration. Nr4a3 expression is reduced in adipose tissue of diabetic rodents; however, whether reduced adipose Nr4a3 contributes to adipose dysfunction, increased adiposity, and T2D remains unclear. Here, we generated global Nr4a3-deficient mice to investigate its role in adipose function and MAPK signaling. Methods: We generated Nr4a3 knock-out mice (C57BL/6J background) maintained on a standard chow diet. Weight analysis and glucose testing were performed every four weeks from week 8 to 28. H&E staining analyzed adipocyte size and morphology. Mitochondrial respiration of muscle, liver, and adipose tissue was measured using Oroboros (O2k). qPCR and western blots identified genes contributing to the phenotype. Results: Male and female Nr4a3-deficient mice exhibited elevated non-fasting glucose and glucose intolerance, with no change in body length or food intake. Male Nr4a3-deficient mice showed 50% increased weight gain from enlarged adipose depots containing adipocytes 20% larger than controls. Using O2k, we observed impaired adipocyte mitochondrial respiration in Nr4a3-deficient mice. Mechanistically, Nr4a3 deletion reduced MEK1 mRNA and protein, a key ERK1/2 activator. Reduced ERK1/2 activation was consistent with decreased DRP1, PLIN, and HSL phosphorylation, regulators of mitochondrial fission and adipogenesis. Conclusion: Nr4a3 acts as a transcriptional regulator of MEK1 in adipose tissue, reducing ERK1/2 phosphorylation. This decrease lowers HSL, PLIN, and DRP1 phosphorylation, dysregulating lipolysis and respiration. These findings provide new insight into Nr4a3-regulated adipocyte function. Reduced Nr4a3 in diabetic adipose tissue may contribute to increased adiposity and T2D. Disclosure P. Ellsworth: None. J. Carter: None. K. Wieland: None. K.H. Hess: None. J. Herring: None. E.D. Marchant: None. J. Saito: None. N. Walker: None. K. Whalen: None. Y.Y. Cao: None. Q. Yang: None. J. Tessem: None.