An N-Salicyloyl Tryptamine Derivative (Compound 18) Improves Spermatogenic Impairment in Obese Mice via Regulating Insulin Resistance and Enhancing Sertoli Cell Glycolysis.
OBJECTIVE This study aimed to investigate the therapeutic potential of compound 18, an N-salicyloyl tryptamine derivative with established anti-neuroinflammatory and neuroprotective properties, in ameliorating male reproductive dysfunction induced by high-fat diet (HFD) in obese mice and to elucidate the underlying mechanisms. METHODS Male mice were fed a HFD to induce obesity and subsequently treated with compound 18 at doses of 25 or 50 mg/kg. Systemic metabolic parameters including body weight, blood glucose, insulin, and lipid profiles were measured. Histopathological assessments were conducted on liver, adipose tissue, testes, and epididymis. Molecular analyses were performed to evaluate the expression of markers related to proliferation (PCNA), apoptosis (BAX and Bcl-2), components of the insulin signaling pathway (IGF1, IGF1R), and key glycolytic enzymes (HK2, PKM2, LDHA). RESULTS Administration of compound 18 led to significant and dose-dependent improvements in systemic metabolism, characterized by reductions in body weight, blood glucose, insulin levels, and lipid parameters. The compound also attenuated hepatic steatosis and adipocyte hypertrophy, while notably restoring testicular and epididymal tissue architecture. At the molecular level, compound 18 up-regulated the proliferative marker PCNA, modulated apoptosis-related proteins (down-regulating Bax and up-regulating Bcl-2), enhanced insulin sensitivity-as indicated by increased IGF1R and decreased IGF1 expression-and augmented glycolytic capacity in Sertoli cells through elevated expression of HK2, PKM2, and LDHA. CONCLUSION These results demonstrate that compound 18 effectively alleviates HFD-induced spermatogenic dysfunction concomitantly with ameliorating testicular insulin resistance and promoting glycolytic flux in Sertoli cells.