Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses
Abstract Background Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study soug...
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BMC
2023-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-023-00669-8 |
| _version_ | 1797789691572912128 |
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| author | Ling Li Li Li Ying Shao Runyu Du Ling Li Xiaoguang Shi Yu Bai |
| author_facet | Ling Li Li Li Ying Shao Runyu Du Ling Li Xiaoguang Shi Yu Bai |
| author_sort | Ling Li |
| collection | DOAJ |
| description | Abstract Background Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM. Methods A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10–6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells. Results Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM. Conclusion Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment. |
| first_indexed | 2024-03-13T01:54:17Z |
| format | Article |
| id | doaj.art-37b6e2ace4b940d7ad6fe851af939fcd |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-03-13T01:54:17Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-37b6e2ace4b940d7ad6fe851af939fcd2023-07-02T11:18:46ZengBMCMolecular Medicine1528-36582023-06-0129111710.1186/s10020-023-00669-8Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analysesLing Li0Li Li1Ying Shao2Runyu Du3Ling Li4Xiaoguang Shi5Yu Bai6Department of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityDepartment of Endocrinology, Shengjing Hospital of China Medical UniversityAbstract Background Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM. Methods A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10–6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells. Results Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM. Conclusion Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment.https://doi.org/10.1186/s10020-023-00669-8Calcium/calmodulin dependent protein kinase IVGestational diabetes mellitusInsulin resistanceTrophoblast cellsAutophagymetabolomics |
| spellingShingle | Ling Li Li Li Ying Shao Runyu Du Ling Li Xiaoguang Shi Yu Bai Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses Molecular Medicine Calcium/calmodulin dependent protein kinase IV Gestational diabetes mellitus Insulin resistance Trophoblast cells Autophagy metabolomics |
| title | Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses |
| title_full | Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses |
| title_fullStr | Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses |
| title_full_unstemmed | Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses |
| title_short | Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses |
| title_sort | calcium calmodulin dependent protein kinase iv in trophoblast cells under insulin resistance functional and metabolomic analyses |
| topic | Calcium/calmodulin dependent protein kinase IV Gestational diabetes mellitus Insulin resistance Trophoblast cells Autophagy metabolomics |
| url | https://doi.org/10.1186/s10020-023-00669-8 |
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