Neuroligin-3: A Novel Exercise-Induced Secreted Factor Enhancing Insulin Sensitivity in Obese Insulin-Resistant Mice

The salutary effects of physical exercise in mitigating metabolic disorders, particularly type 2 diabetes, are well recognized. Several studies have demonstrated that endurance training boosts the production of exercise-induced myokines, which are pivotal for interorgan communication enhancing insulin sensitivity. However, several challenges, including an incomplete understanding of underlying molecular mechanisms, hinder their therapeutic application. Here, we have identified a potential exercise-induced mediator, neuroligin-3 (NLGN3), that enhances insulin sensitivity and abrogates inflammation. Mechanistic studies in white adipocytes revealed that NLGN3 interacts with neurexin-3 (NRXN3) to modulate their function and insulin sensitivity, while in macrophages, NLGN3 engages with NRXN1 to attenuate inflammation and promote an anti-inflammatory phenotype. Administration of NLGN3 in high-fat diet (HFD)-fed mice significantly ameliorated obesity-induced visceral adipose tissue dysfunction and insulin insensitivity; however, these attributes are markedly abolished in NRXN1/3-deficient mice. In addition, elevated serum NLGN3 levels following swimming exercise training correlated with improved metabolic outcomes in HFD-fed obese diabetic mice. These findings suggest that NLGN3 may serve as a key mediator of exercise-induced metabolic benefits and highlight the NLGN3-NRXN1/3 pathway as a promising target for managing obesity-induced insulin resistance. ARTICLE HIGHLIGHTS: This study aimed to identify novel exercise-induced myokines and their role in improving insulin sensitivity and reducing inflammation. We identified neuroligin-3 (NLGN3) as an exercise-induced mediator that enhances insulin sensitivity and alleviates inflammation. Exercise-induced NLGN3 upregulation or recombinant NLGN3 administration improved metabolic function in high-fat diet-fed mice via neurexin-1 and -3 (NRXN1/3), but these benefits were lost upon NRXN1/3 ablation. NLGN3 emerges as a key mediator of exercise-driven metabolic benefits and a promising therapeutic target for obesity-associated insulin resistance.