Semaglutide treatment for Male Obesity-Associated Hypogonadism alters DNA methylation and miRNA patterns.

Male obesity-associated secondary hypogonadism (MOSH) is a prevalent condition in severely obese men, often persisting even after surgical weight loss. Current interventions primarily focus on testosterone replacement, which doesn't address underlying metabolic dysfunction. This study explores the epigenetic landscape, specifically DNA methylation and miRNA expression, as a potential mechanism through which weight-loss drugs like semaglutide might exert their benefits beyond simple weight reduction, addressing a gap in understanding MOSH pathophysiology.

This exploratory study investigated epigenetic changes in MOSH patients treated with Semaglutide. Samples were categorized into a control group (n=2), a MOSH group (n=7), and a follow-up group (n=4). DNA methylation analysis was performed on all 13 samples. miRNA sequencing was conducted on a subset (n=11), including 2 controls, 7 MOSH, and 2 follow-up. limma was used for differentially expressed miRNAs (DEMs), and methylation β values identified differentially methylated genes (DMGs). Functional enrichment used clusterProfiler, followed by regulatory and protein-protein interaction (PPI) network analyses.

A total of 6 differentially expressed miRNAs (DEMs) were identified. Target genes of these DEMs were primarily enriched in pathways such as ATP binding, phosphorylation, cell adhesion, and Glycosphingolipid biosynthesis. 80 differentially methylated genes (DMGs) were screened, with the largest number found on the X chromosome.

In the regulatory network of DMGs and DEMs, hsa-miR-423-5p emerged as a key regulator, influencing most of the identified DMGs. The protein-protein interaction (PPI) network highlighted DPP6, DPP10, CACNA1C, and CNTNAP2 as proteins with the strongest connectivity. Notably, differential CpG methylation changes were observed on chromosome 7, suggesting a specific region of epigenetic alteration in MOSH.