دورية أكاديمية
MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance
| العنوان: | MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance |
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| المؤلفون: | Becker-Greene, Dakota, Li, Hao, Perez-Cremades, Daniel, Wu, Winona, Bestepe, Furkan, Ozdemir, Denizhan, Icli, Basak |
| بيانات النشر: | Springer Basel Ag |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Angiogenesis, Type 2 diabetes, Insulin resistance, Brown adipose tissue, MicroRNA-409-3p, Glucose-Homeostasis, Obesity, Fat, Hypoxia, Mice, Adipogenesis, Inflammation, Sensitivity, Metastasis, Disorders |
| الوصف: | Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity. ; [NIH P30DK034854] ; We thank Lay-Hong Ang and Aniket Gad for Confocal Microscopy technical assistance (NIH P30DK034854), Yevgenia Tesmenitsky for i.v. injections, Merve Kurt with her technical assistance in EC scratch assays. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1420-682X 1420-9071 |
| العلاقة: | Cellular And Molecular Life Sciences; Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı; https://doi.org/10.1007/s00018-021-03960-1Test; https://hdl.handle.net/20.500.12831/6443Test; WOS:000711347900003; 2-s2.0-85118184984; PubMed: 34698882 |
| DOI: | 10.1007/s00018-021-03960-1 |
| الإتاحة: | https://doi.org/10.1007/s00018-021-03960-1Test https://doi.org/20.500.12831/6443Test https://hdl.handle.net/20.500.12831/6443Test |
| حقوق: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.265598E5 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 1420682X 14209071 |
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| DOI: | 10.1007/s00018-021-03960-1 |