Abstract
Metabolic syndrome (MetS), which is associated with chronic inflammation, predisposes males to hypogonadism and subfertility. The underlying mechanism of these pathologies remains poorly understood. Homozygous leptin-resistant obese db/db mice are characterized by small testes, low testicular testosterone, and a reduced number of Leydig cells. Here we report that IL-1β, CCL2 (also known as MCP-1), and corticosterone concentrations were increased in the testes of db/db mice relative to those in WT controls. Cultured murine and human Leydig cells responded to cytokine stress with increased CCL2 release and apoptotic signals. Chemical inhibition of CCL2 rescued Leydig cell function in vitro and in db/db mice. Consistently, we found that Ccl2-deficient mice fed with a high-energy diet were protected from testicular dysfunction compared with similarly fed WT mice. Finally, a cohort of infertile men with a history of MetS showed that reduction of CCL2 plasma levels could be achieved by weight loss and was clearly associated with recovery from hypogonadism. Taken together, we conclude that CCL2-mediated chronic inflammation is, to a large extent, responsible for the subfertility in MetS by causing damage to Leydig cells.
Highlights
Infertility affects 10% of couples worldwide, and male factors contribute to more than 40% of the infertility cases [1, 2]
This study shows that chronic inflammation in full Metabolic syndrome (MetS) can cause Leydig cell dysfunction and result in hypogonadism (Supplemental Figure 6)
Increased IL-1β and C motif chemokine ligand 2 (CCL2) in adipose tissue and testes were associated with significant impairment of sperm quality and fertility as well as deterioration of androgen synthesis, which was caused by a clear reduction of Leydig cells
Summary
Infertility affects 10% of couples worldwide, and male factors contribute to more than 40% of the infertility cases [1, 2]. In adipose and liver tissue, enhanced expression of tumor necrosis factor–α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and C-C motif chemokine ligand 2 (CCL2), known as monocyte chemoattractant protein-1 (MCP-1), was reported [20,21,22,23]. These inflammatory factors are causative and predictive for many organ-specific diseases associated with MetS [24], yet the mechanism linking chronic inflammation to testicular impairment in the setting of MetS has not been addressed
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