Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation
Abstract Background MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in hig...
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BMC
2024-11-01
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| Series: | Immunity & Ageing |
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| Online Access: | https://doi.org/10.1186/s12979-024-00485-6 |
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| author | Keerthana Chithanathan Monika Jürgenson Katrina Ducena Anu Remm Kalev Kask Ana Rebane Li Tian Alexander Zharkovsky |
| author_facet | Keerthana Chithanathan Monika Jürgenson Katrina Ducena Anu Remm Kalev Kask Ana Rebane Li Tian Alexander Zharkovsky |
| author_sort | Keerthana Chithanathan |
| collection | DOAJ |
| description | Abstract Background MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence. Results Wild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo’s therapeutic efficacy on miR-146a. Conclusion Elocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence. |
| format | Article |
| id | doaj-art-ed07ab84635d4886b4a291dc8a041d30 |
| institution | OA Journals |
| issn | 1742-4933 |
| language | English |
| publishDate | 2024-11-01 |
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| series | Immunity & Ageing |
| spelling | doaj-art-ed07ab84635d4886b4a291dc8a041d302025-08-20T02:33:02ZengBMCImmunity & Ageing1742-49332024-11-0121112110.1186/s12979-024-00485-6Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulationKeerthana Chithanathan0Monika Jürgenson1Katrina Ducena2Anu Remm3Kalev Kask4Ana Rebane5Li Tian6Alexander Zharkovsky7Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of TartuDepartment of Pharmacology, Institute of Biomedicine and Translational Medicine, University of TartuInstitute of Science and Technology, University of TartuDepartment of Biomedicine, Institute of Biomedicine and Translational Medicine, University of TartuAdge Pharmaceuticals IncDepartment of Biomedicine, Institute of Biomedicine and Translational Medicine, University of TartuDepartment of Physiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of TartuDepartment of Pharmacology, Institute of Biomedicine and Translational Medicine, University of TartuAbstract Background MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence. Results Wild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo’s therapeutic efficacy on miR-146a. Conclusion Elocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.https://doi.org/10.1186/s12979-024-00485-6High-fat dietHypothalamusMicrogliaSenescencemiR-146aElocalcitol |
| spellingShingle | Keerthana Chithanathan Monika Jürgenson Katrina Ducena Anu Remm Kalev Kask Ana Rebane Li Tian Alexander Zharkovsky Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation Immunity & Ageing High-fat diet Hypothalamus Microglia Senescence miR-146a Elocalcitol |
| title | Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation |
| title_full | Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation |
| title_fullStr | Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation |
| title_full_unstemmed | Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation |
| title_short | Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation |
| title_sort | elocalcitol mitigates high fat diet induced microglial senescence via mir 146a modulation |
| topic | High-fat diet Hypothalamus Microglia Senescence miR-146a Elocalcitol |
| url | https://doi.org/10.1186/s12979-024-00485-6 |
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