N-salicyloyl tryptamine derivative ameliorates spermatogenic dysfunction in obese mice by attenuating insulin resistance, enhancing Sertoli cell glycolysis, and inhibiting apoptosis: an in vivo and in vitro study

Background Obesity impairs male reproductive function, yet effective protective strategies are limited. Compound 51 is a novel N-salicyloyl tryptamine derivative whose role in spermatogenic function is unknown. This study aimed to determine whether it protects against obesity-induced spermatogenic dysfunction. Methods Employing a combined in vivo and in vitro approach, we first evaluated compound 51 in a high-fat diet-induced obese mouse model, assessing systemic metabolism, reproductive phenotype, and molecular changes in testes. To investigate the underlying cellular mechanisms suggested by the in vivo findings, parallel experiments were conducted in palmitic acid-injured TM4 Sertoli cells, focusing on insulin signaling and glycolytic function. Results In vivo , compound 51 administration significantly improved body weight, semen quality, testicular/epididymal morphology, and hormone levels (testosterone, follicle-stimulating hormone, inhibin B). It dose-dependently modulated apoptosis markers (downregulated Bax, upregulated Bcl-2/PCNA), enhanced testicular insulin sensitivity (reduced insulin-like growth factor 1 (IGF1) and elevated its receptor IGF1R), and increased glycolytic enzyme expression (hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A). In vitro , compound 51 promoted proliferation, improved insulin sensitivity, and enhanced glycolytic activity in PA-injured TM4 cells, thereby ameliorating Sertoli cell dysfunction. Conclusion Compound 51 ameliorates obesity-induced spermatogenic dysfunction by enhancing testicular insulin sensitivity and promoting glycolytic flux in Sertoli cells.