Kisspeptin-10 Alleviates Obesity-induced Testicular Oxidative Stress and Mitochondrial Dysfunction via Modulation of Mitophagy and Autophagy Signaling.

Abstract

Obesity impairs male reproductive function via oxidative stress and mitochondrial dysfunction. Kisspeptin-10 may regulate redox balance and mitochondrial homeostasis, but its role in obesity-related testicular dysfunction remains unclear. This study aimed to investigate whether Kisspeptin-10 ameliorates obesity-induced testicular oxidative stress and sperm dysfunction, with particular emphasis on mitophagy, autophagy, and apoptosis-related pathways. Forty male Sprague Dawley rats were divided into four groups: Control, Obesity, Kisspeptin-10, and Obesity+Kisspeptin-10. Obesity was induced by feeding rats a high-fat diet (60% kcal from fat) for 12 weeks. At the end of week 12, rats with a Lee index ≥ 300 were considered obese. During the subsequent 4-week treatment period, the Obesity and Obesity+Kisspeptin-10 groups continued to receive the high-fat diet, whereas the Control and Kisspeptin-10 groups continued to receive the standard diet. Kisspeptin-10 (50 nmol/kg, i.p.) was administered to both the Kisspeptin-10 and Obesity+Kisspeptin-10 groups from week 13 to week 16. Oxidative stress markers in the testes, sperm parameters, sperm mitochondrial membrane potential (MMP), and sperm deoxyribonucleic acid (DNA) integrity were assessed; in addition, protein expression levels of markers for mitophagy, autophagy, and apoptosis were evaluated. Obesity impaired antioxidant capacity, sperm quality, mitochondrial function, and reproductive organ weight, while increasing lipid peroxidation and sperm abnormalities. Kisspeptin-10 reduced oxidative stress by lowering malondialdehyde (MDA) and increasing glutathione (GSH) levels, improved sperm motility and concentration, reduced tail abnormal sperm ratio, showed a non-significant tendency toward partial restoration of mitochondrial function, decreased DNA damage, and increased prostate weight. It was also associated with increased expression of the mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1) and Prohibitin 2 (PHB2), and increased Beclin-1 expression, with no significant effects on Parkin, Microtubule-associated protein 1 light chain 3-II (LC3-II), or apoptosis-related proteins. Kisspeptin-10 may alleviate obesity-induced testicular dysfunction, potentially through modulation of redox balance and mitochondrial quality-control mechanisms, including changes in mitophagy- and autophagy-related protein expression. Although these findings suggest that Kisspeptin-10 is a promising candidate for the treatment of obesity-related male infertility, its effects on downstream autophagy-related signaling and apoptosis appear to be limited.