Melatonin protects mouse testes from palmitic acid‐induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner

<jats:title>Abstract</jats:title><jats:p>Palmitic acid (PA), the main component of dietary saturated fat, has been known to increase in patients with obesity, and PA‐induced lipotoxicity may contribute to obesity‐related male infertility. Melatonin has beneficial effects on reproductive processes; however, the effect and the underlying molecular mechanism of melatonin's involvement in PA‐induced cytotoxicity in the testes are poorly understood. Our findings showed that lipotoxicity was observed in mouse testes after long‐term PA treatment and that melatonin therapy restored spermatogenesis and fertility in these males. Moreover, melatonin therapy suppressed PA‐induced apoptosis by modulating apoptosis‐associated proteins such as Bcl2, Bax, C‐Caspase3, C‐Caspase12, and CHOP in type B spermatogonial stem cells. Changes in the expression of endoplasmic reticulum (ER) stress markers (p‐IRE1, p‐PERK, ATF4) and intracellular Ca<jats:sup>2+</jats:sup> levels showed that melatonin relieved PA‐induced ER stress. Mechanistically, melatonin stimulated the expression and nuclear translocation of SIRT1 through its receptors and prevented PA‐induced ROS production and mitochondrial dysfunction via SIRT1 signaling pathway. Furthermore, melatonin promoted SIRT1‐mediated p53 deacetylation, thereby relieving G2/M arrest in response to PA‐stimulated DNA damage. Collectively, these findings indicate that melatonin protects the testes from PA‐induced lipotoxicity through the activation of SIRT1, which alleviates oxidative stress, ER stress, mitochondrial dysfunction, and DNA damage.</jats:p>