NEGR1 deficiency disrupts lipid metabolism and steroidogenesis in Leydig cells, linking testosterone to behavior

Neuronal growth regulator 1 (NEGR1) has been identified as a critical risk factor for major depressive disorders in humans. Although NEGR1 is predominantly expressed in the brain, its deletion in mice (Negr1^-/-) results in abnormalities in peripheral tissues, suggesting a role beyond the nervous system, particularly in intracellular lipid trafficking. However, the role of NEGR1 in testosterone production has not yet been elucidated. Here, we demonstrate that Negr1^-/- mice exhibit significantly reduced serum and testicular testosterone levels, accompanied by diminished male reproductive behaviors. The expression of key testosterone-synthesizing enzymes was downregulated in Leydig cells, and histological analysis revealed disorganized testicular and epididymal structures with lipid droplet accumulation in testicular cells. Additionally, Negr1^-/- mice displayed a significant increase in abnormal sperm morphology. Notably, testosterone supplementation alleviated their impaired sexual behaviors and mitigated anxiety- and depression-like phenotypes. These findings highlight a crucial role for NEGR1 in testicular function, particularly in testosterone production and spermatogenesis, underscoring the intricate link between hormonal balance and mental health.