The Metabolic Syndrome (MetS) reportedly leads to hypogonadism and male subfertility. However, inherent mechanisms are under discussion. Inflammation through infections contributes to nearly 15% of total cases of human infertility. As emerging evidence shows MetS leads to reduced male fertility, the role of inflammation in the MetS-related male subfertility needs to be investigated, and dysregulation of certain pro-inflammatory factor(s) could be held responsible for the failed reproductivity of MetS-stressed subjects. In this study, leptin-resistant mice were used as a model to detect signs of testicular inflammation and impaired Leydig cell function. Mouse and cell models were adopted to study Leydig cells and epididymal sperm in the context of full MetS syndrome. Male BKS(D)-Leprdb+/+/JOrlRj (db/db) mice exhibited MetS and testicular dysfunction after the age of 6 weeks. They were characterized by small testis, low testosterone level, and impaired Leydig cell function. Inflammation was present in the testis of db/db mice, as indicated by upregulated IL-1beta and MCP-1. Interestingly, the ratio of M1 to M2 macrophages was reduced while testicular corticosterone concentrations were enhanced in db/db mice as opposed to wildtype controls. In vitro treatment of mouse Leydig cells with IL-1beta enhanced MCP-1 secretion along with increased caspase 3 expression that is activated in the cell as an indicator for apoptosis. Leydig cell function was rescued by chemical inhibition of MCP-1. Meanwhile, reduced expression of ATF6 indicates involvement of ER stress in the progression of subfertility in db/db mice.Collectively, these findings suggest that the inflammatory environment and ER stress in testis are partially responsible for the damaged fertility in mice with MetS. Considering the critical role of MCP-1, inhibition of MCP-1 may be a putative target for therapeutic intervention in treatment of MetS associated subfertility.
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