Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells
Abstract Background Accumulating evidence indicates a key role of Sertoli cell (SC) malfunction in spermatogenesis impairment induced by obesity. Nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) is expressed in SCs, but the role of NLRP3 in the pathological proce...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Inflammation and Regeneration |
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| Online Access: | https://doi.org/10.1186/s41232-022-00203-z |
| _version_ | 1818504952119558144 |
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| author | Yang Mu Tai-lang Yin Yan Zhang Jing Yang Yan-ting Wu |
| author_facet | Yang Mu Tai-lang Yin Yan Zhang Jing Yang Yan-ting Wu |
| author_sort | Yang Mu |
| collection | DOAJ |
| description | Abstract Background Accumulating evidence indicates a key role of Sertoli cell (SC) malfunction in spermatogenesis impairment induced by obesity. Nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) is expressed in SCs, but the role of NLRP3 in the pathological process of obesity-induced male infertility remains unclear. Methods NLRP3-deficient mice were fed a high-fat diet for 24 weeks to establish obesity-related spermatogenesis impairment. In another set of experiments, a lentiviral vector containing a microRNA (miR)-451 inhibitor was injected into AMP-activated protein kinase α (AMPKα)-deficient mouse seminiferous tubules. Human testis samples were obtained by testicular puncture from men with obstructive azoospermia whose samples exhibited histologically normal spermatogenesis. Isolated human SCs were treated with palmitic acid (PA) to mimic obesity model in vitro. Results Increased NLRP3 expression was observed in the testes of obese rodents. NLRP3 was also upregulated in PA-treated human SCs. NLRP3 deficiency attenuated obesity-related male infertility. SC-derived NLRP3 promoted interleukin-1β (IL-1β) secretion to impair testosterone synthesis and sperm performance and increased matrix metalloproteinase-8 (MMP-8) expression to degrade occludin via activation of nuclear factor-kappa B (NF-κB). Increased miR-451 caused by obesity, decreased AMPKα expression and sequentially increased NADPH oxidase activity were responsible for the activation of NLRP3. miR-451 inhibition protected against obesity-related male infertility, and these protective effects were abolished by AMPKα deficiency in mice. Conclusions NLRP3 promoted obesity-related spermatogenesis impairment. Increased miR-451 expression, impaired AMPKα pathway and the subsequent ROS production were responsible for NLRP3 activation. Our study provides new insight into the mechanisms underlying obesity-associated male infertility. |
| first_indexed | 2024-12-10T21:44:10Z |
| format | Article |
| id | doaj.art-f40d185ff41c4948954a057301c8ceb6 |
| institution | Directory Open Access Journal |
| issn | 1880-8190 |
| language | English |
| last_indexed | 2024-12-10T21:44:10Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Inflammation and Regeneration |
| spelling | doaj.art-f40d185ff41c4948954a057301c8ceb62022-12-22T01:32:25ZengBMCInflammation and Regeneration1880-81902022-08-0142111810.1186/s41232-022-00203-zDiet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cellsYang Mu0Tai-lang Yin1Yan Zhang2Jing Yang3Yan-ting Wu4Reproductive Medicine Center, Renmin Hospital of Wuhan UniversityReproductive Medicine Center, Renmin Hospital of Wuhan UniversityDepartment of Clinical Laboratory, Renmin Hospital of Wuhan UniversityReproductive Medicine Center, Renmin Hospital of Wuhan UniversityInstitute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan UniversityAbstract Background Accumulating evidence indicates a key role of Sertoli cell (SC) malfunction in spermatogenesis impairment induced by obesity. Nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) is expressed in SCs, but the role of NLRP3 in the pathological process of obesity-induced male infertility remains unclear. Methods NLRP3-deficient mice were fed a high-fat diet for 24 weeks to establish obesity-related spermatogenesis impairment. In another set of experiments, a lentiviral vector containing a microRNA (miR)-451 inhibitor was injected into AMP-activated protein kinase α (AMPKα)-deficient mouse seminiferous tubules. Human testis samples were obtained by testicular puncture from men with obstructive azoospermia whose samples exhibited histologically normal spermatogenesis. Isolated human SCs were treated with palmitic acid (PA) to mimic obesity model in vitro. Results Increased NLRP3 expression was observed in the testes of obese rodents. NLRP3 was also upregulated in PA-treated human SCs. NLRP3 deficiency attenuated obesity-related male infertility. SC-derived NLRP3 promoted interleukin-1β (IL-1β) secretion to impair testosterone synthesis and sperm performance and increased matrix metalloproteinase-8 (MMP-8) expression to degrade occludin via activation of nuclear factor-kappa B (NF-κB). Increased miR-451 caused by obesity, decreased AMPKα expression and sequentially increased NADPH oxidase activity were responsible for the activation of NLRP3. miR-451 inhibition protected against obesity-related male infertility, and these protective effects were abolished by AMPKα deficiency in mice. Conclusions NLRP3 promoted obesity-related spermatogenesis impairment. Increased miR-451 expression, impaired AMPKα pathway and the subsequent ROS production were responsible for NLRP3 activation. Our study provides new insight into the mechanisms underlying obesity-associated male infertility.https://doi.org/10.1186/s41232-022-00203-zAMPKαMicroRNANLRP3, ObesitySertoli cells |
| spellingShingle | Yang Mu Tai-lang Yin Yan Zhang Jing Yang Yan-ting Wu Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells Inflammation and Regeneration AMPKα MicroRNA NLRP3, Obesity Sertoli cells |
| title | Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells |
| title_full | Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells |
| title_fullStr | Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells |
| title_full_unstemmed | Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells |
| title_short | Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells |
| title_sort | diet induced obesity impairs spermatogenesis the critical role of nlrp3 in sertoli cells |
| topic | AMPKα MicroRNA NLRP3, Obesity Sertoli cells |
| url | https://doi.org/10.1186/s41232-022-00203-z |
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