62-PUB: The Mechanism of IGF2-IGF2R Signaling in Regulating Testosterone Synthesis in Testicular Leydig Cells

Introduction and Objective: This study aims to explore how the IGF2 signal affects testosterone synthesis in Leydig cells and to further investigate its mechanism in male hypogonadism and obesity. Methods: A model of obese male mice was created by combining bilateral orchiectomy with a high-fat diet, and compared with sham surgery high-fat and normal chow groups for weight gain, serum hormone levels, and metabolic indicators.IGF2R expression in Leydig cells was detected. The distribution of cholesterol esters in Leydig cells was detected by confocal microscopy. ELISA was utilized to measure testosterone levels. QPCR and Western Blot were used to analyze HSD17B3 and CYP7A1 levels. Finally, IGF2 supplementation therapy was employed. Results: Compared to sham surgery, orchiectomy-induced obese mice showed faster weight gain under high-fat diets, with reduced serum testosterone, DHT, estradiol, and IGF2 levels. Igf2 was mainly expressed in Leydig cells, with Igf2r similarly expressed. IGF2 and IGF2R expression in Leydig cells correlated with key enzymes in testosterone synthesis. Cellular experiments confirmed that IGF2R knockout reduced testosterone synthesis, while overexpression enhanced it. IGF2 supplementation activated AMPK, promoting lipophagy and increasing free cholesterol, which was converted to testosterone precursors. This improved testosterone synthesis and mitigated obesity in orchiectomy-induced mice. Conclusion: The IGF2 signal has a positive regulatory effect on testosterone synthesis in Leydig cells. IGF2 activates AMPK through the IGF2R signal, promotes lipophagy in Leydig cells, enhances cholesterol uptake and metabolism, and ultimately promotes testosterone synthesis. In the obese state, the weakening of the IGF2-IGF2R signal may lead to reduced testosterone synthesis, which may be associated with obesity-related hypogonadism. Disclosure W. Gui: None. C. Zhou: None. D. Wu: None. X. Lin: None. Funding National Natural Science Foundation of China (82200638)