Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome

Area of Science:

• Reproductive biology
• Endocrinology
• Immunology

Background:

• Metabolic syndrome (MetS) is linked to chronic inflammation, male hypogonadism, and subfertility.
• The precise mechanisms driving these pathologies in MetS are not fully understood.
• Obese, leptin-resistant mice exhibit testicular dysfunction, including reduced testosterone and Leydig cell counts.

Purpose of the Study:

• To investigate the role of chronic inflammation and specific mediators in MetS-associated male subfertility.
• To elucidate the impact of CCL2 (MCP-1) on Leydig cell function and testicular health.
• To explore potential therapeutic strategies targeting CCL2.

Main Methods:

• Analysis of testicular inflammatory markers (IL-1β, CCL2, corticosterone) in db/db mice versus WT controls.
• In vitro studies using murine and human Leydig cells exposed to cytokine stress.
• Pharmacological inhibition of CCL2 in vitro and in vivo (db/db mice).
• Assessment of testicular function in Ccl2-deficient mice on a high-energy diet.
• Correlation analysis of plasma CCL2 levels, weight loss, and hypogonadism recovery in infertile men with MetS.

Main Results:

• db/db mice testes showed elevated IL-1β, CCL2, and corticosterone.
• Cultured Leydig cells released CCL2 and showed apoptotic signals under cytokine stress.
• CCL2 inhibition restored Leydig cell function in vitro and in db/db mice.
• Ccl2-deficient mice on a high-energy diet were protected from testicular dysfunction.
• Weight loss in infertile men with MetS reduced plasma CCL2 and improved hypogonadism.

Conclusions:

• CCL2-mediated chronic inflammation significantly contributes to Leydig cell damage and subfertility in Metabolic Syndrome.
• Targeting CCL2 presents a potential therapeutic avenue for restoring male reproductive health in MetS patients.
• Weight loss is an effective strategy to reduce CCL2 levels and ameliorate hypogonadism in men with MetS.