Nicotinamide mononucleotide treatment improves spermatogenesis in obese mice by reducing lysine acetylation of lactate dehydrogenase C

Obesity is associated with impaired spermatogenesis and decreased sperm quality, in part through reducing Sertoli cells (SCs) lactate and nicotinamide adenine dinucleotide (NAD⁺) production. It is not known whether nicotinamide mononucleotide (NMN) treatment improves spermatogenesis. In the present study, NMN improved lipid metabolism and enhanced spermatogenesis in obese mice, alleviated SCs dysfunction in vivo and in vitro. Label-free quantitative acetylomics analysis of mouse testes suggested that protein acetylation influenced both the structural and functional properties of metabolic proteins. The beneficial effects of NMN were due in part to changes in the acetylation of glycolysis-related proteins. Furthermore, multi-omics and correlation analyses demonstrated that interactions among the gut microbiota, metabolites, spermatogenesis, and LDHC acetylation mediated the beneficial effects of NMN. Importantly, we found that NMN treatment reduced acetylation of the lysine residues 5, 17, and 90 of LDHC, which plays a critical role in SC lactate production in obesity. Collectively, our findings show that NMN supplementation improves sperm quality in obese mice by decreasing LDHC acetylation, thereby increasing Sertoli cell lactate and NAD⁺ production.