Semaglutide treatment in MOSH is associated with altered DNA methylation patterns of genes related to glycolipid metabolism.

Male obesity-associated secondary hypogonadism(MOSH) is a common disease among severely obese male patients. Although surgical interventions have demonstrated clinical benefits, a subset of patients continue to experience MOSH following surgery. Therefore, this study aims to investigate epigenetic changes associated with the use of the weight-loss drug Semaglutide in MOSH, focusing on DNA methylation and miRNA expression. In this exploratory study, samples were classified into three groups: a control group (n = 2), a MOSH group (n = 7), and a follow-up group (n = 4). DNA methylation analysis was performed on all samples, while miRNA sequencing was conducted on a subset of the samples: 2 from the control group, 7 from the MOSH group, and 2 from the follow-up group. Differentially expressed miRNAs (DEMs) were analyzed through the R package "limma", and the methylation level of CpG sites was analyzed based on the methylation β value, obtaining differentially methylated genes (DMGs). The functional enrichment analysis of miRNA target genes and methylation change genes was conducted using the R package "clusterProfiler". Finally, the regulatory networks of miRNA and methylation genes as well as the protein-protein interaction (PPI) network were analyzed. A total of 6 DEMs were screened out. The target genes of these DEMs were mainly enriched in pathways such as ATP binding, phosphorylation, cell adhesion, and Glycosphingolipid biosynthesis. Eighty DMGs were identified, and the largest number of DMGs were found in the X chromosome. In the regulatory network of DMGs and DEMs, hsa-miR-423-5p regulates most of these DMGs. Moreover, the PPI network shows that DPP6, DPP10, CACNA1C, and CNTNAP2 are the proteins with the strongest connectivity. Notably, differential CpG methylation changes were observed on chromosome 7, indicating a potential region of epigenetic alteration in MOSH; however, the biological and functional relevance of these changes remains unclear. Collectively, these findings suggest that Semaglutide treatment in MOSH may be associated with concurrent alterations in DNA methylation and miRNA expression, implicating genes related to energy and glycolipid metabolism, including DPP6, DPP10, CACNA1C, and CNTNAP2. These results are exploratory and hypothesis-generating, providing preliminary observations to inform future validation studies.