Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1
A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, s...
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Elsevier
2025-07-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525003247 |
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| author | Xiaohui Zhang Xinyu Tang Ting Gao Yuanfang Guo Guangping Lu Qingbo Liu Jiahao Li Jie Wang Mingrui Liu Dongmei Zhang Yufeng Tang Junlian Gu |
| author_facet | Xiaohui Zhang Xinyu Tang Ting Gao Yuanfang Guo Guangping Lu Qingbo Liu Jiahao Li Jie Wang Mingrui Liu Dongmei Zhang Yufeng Tang Junlian Gu |
| author_sort | Xiaohui Zhang |
| collection | DOAJ |
| description | A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO+/–) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM. |
| format | Article |
| id | doaj-art-e8395c8a87e24906a5f674e2308744c4 |
| institution | Kabale University |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-e8395c8a87e24906a5f674e2308744c42025-08-20T03:50:06ZengElsevierActa Pharmaceutica Sinica B2211-38352025-07-011573591361010.1016/j.apsb.2025.05.018Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1Xiaohui Zhang0Xinyu Tang1Ting Gao2Yuanfang Guo3Guangping Lu4Qingbo Liu5Jiahao Li6Jie Wang7Mingrui Liu8Dongmei Zhang9Yufeng Tang10Junlian Gu11School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaDepartment of Orthopedic Surgery, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China; Corresponding authors.School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Corresponding authors.A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO+/–) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.http://www.sciencedirect.com/science/article/pii/S2211383525003247Sleep fragmentationTesticular injuryMelatonin receptorLipid metabolismFGFR1TAB1 |
| spellingShingle | Xiaohui Zhang Xinyu Tang Ting Gao Yuanfang Guo Guangping Lu Qingbo Liu Jiahao Li Jie Wang Mingrui Liu Dongmei Zhang Yufeng Tang Junlian Gu Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 Acta Pharmaceutica Sinica B Sleep fragmentation Testicular injury Melatonin receptor Lipid metabolism FGFR1 TAB1 |
| title | Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 |
| title_full | Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 |
| title_fullStr | Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 |
| title_full_unstemmed | Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 |
| title_short | Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 |
| title_sort | melatonin receptor 1a alleviates sleep fragmentation aggravated testicular injury in t2dm by suppression of tab1 tak1 complex through fgfr1 |
| topic | Sleep fragmentation Testicular injury Melatonin receptor Lipid metabolism FGFR1 TAB1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525003247 |
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