Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome
| Autor: | Agnieszka Paradowska-Dogan, Sebastian Friedrich Petry, Hans-Christian Schuppe, Sudhanshu Bhushan, Michaela F. Hartmann, Yongsheng Chang, Lanbo Shi, Qingkui Jiang, Christine Wrenzycki, Constanze Christin Maresch, Stefan A. Wudy, Thomas Linn, Petr Houska |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Urology medicine.medical_treatment Reproductive biology Inflammation CCL2 Diabetes Mellitus Experimental Mice 03 medical and health sciences chemistry.chemical_compound Endocrinology 0302 clinical medicine Corticosterone Internal medicine medicine Animals Humans Obesity Chemokine CCL2 Infertility Male Testosterone Metabolic Syndrome Leydig cell business.industry Hypogonadism Leydig Cells General Medicine medicine.disease Mice Inbred C57BL Fertility 030104 developmental biology medicine.anatomical_structure Cytokine chemistry Apoptosis 030220 oncology & carcinogenesis Medicine Chemokines medicine.symptom Metabolic syndrome business Research Article |
| Zdroj: | JCI Insight, Vol 5, Iss 21 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.134882 |
| Popis: | 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. MCP-1/CCL2 upregulation associates with metabolic syndrome–induced male subfertility in both mice and men. |
| Databáze: | OpenAIRE |
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