Metabolic pathways and male fertility: exploring the role of Sertoli cells in energy homeostasis and spermatogenesis

Globalization has driven a surge in noncommunicable diseases, including metabolic disorders, which are major global health challenges. These disorders, fueled by high-calorie diets, sedentary lifestyles, and gut microbiota imbalances, disrupt energy metabolism, gastrointestinal function, and vitamin and trace element homeostasis. Sertoli cells provide the metabolic and structural support essential for germ cell development within the seminiferous epithelium. This review examines how metabolic disorders affect male reproductive health, focusing on glucose, lipid, and vitamin metabolism, as well as the gut-testis axis, in relation to Sertoli cell function and the blood-testis barrier (BTB) integrity. Glucose metabolism in Sertoli cells provides lactate to germ cells, which is crucial for spermatogenesis. However, metabolic stressors, such as diabetes, impair glucose transport and lactate production, compromising energy supply. Lipid metabolism, including fatty acid oxidation and lipid droplet dynamics, is essential for energy homeostasis in Sertoli cells. Moreover, the gut microbiota further influences Sertoli cells and BTB integrity via metabolites, such as short-chain fatty acids, which enhance barrier function and reduce inflammation. Conversely, dysbiosis and microbially derived lipopolysaccharides induce oxidative stress and immune responses, leading to BTB disruption and infertility. Deficiencies or imbalances in the levels of these vitamins and trace elements can impair spermatogenesis. This review highlights the complex interplay between metabolic pathways and Sertoli cell function, their collective impact on male fertility, and provides a basis for developing targeted therapeutic strategies, including metabolic modulators, vitamin supplementation, and gut microbiota interventions, to mitigate the effects of metabolic disorders on spermatogenesis and fertility.