芒果苷通过抑制 PINK1-PRKN 介导的自噬促进 C3H10T1/2 间充质干细胞向棕色脂肪表型分化：涉及 PKA-p38MAPK 信号通路。
PINK1-PRKN mitophagy suppression by mangiferin promotes a brown-fat-phenotype via PKA-p38 MAPK signalling in murine C3H10T1/2 mesenchymal stem cells.
机构信息
Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea; Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea.
Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea; Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea.
出版信息
Metabolism. 2020 Jun;107:154228. doi: 10.1016/j.metabol.2020.154228. Epub 2020 Apr 11.
OBJECTIVE
Mangiferin (MF), a xanthonoid derived from Mangifera indica, has shown therapeutic effects on various human diseases including cancer, diabetes, and obesity. Nonetheless, the influence of MF on non-shivering thermogenesis and its underlying mechanism in browning remains unclear. Here, our aim was to investigate the effects of MF on browning and its molecular mechanisms in murine C3H10T1/2 mesenchymal stem cells (MSCs).
MATERIALS/METHODS: To determine the function of MF on browning, murine C3H10T1/2 MSCs were treated with MF in an adipogenic differentiation cocktail and the thermogenic and correlated metabolic responses were assessed using MF-mediated signalling. Human adipose-derived MSCs were differentiated and treated with MF to confirm its role in thermogenic induction.
RESULTS
MF treatment induced the expression of a brown-fat signature, UCP1, and reduced triglyceride (TG) in C3H10T1/2 MSCs. MF also induced the expression of major thermogenesis regulators: PGC1α, PRDM16, and PPARγ and up-regulated the expression of beiging markers CD137, HSPB7, TBX1, and COX2 in both murine C3H10T1/2 MSCs and human adipose-derived mesenchymal stem cells (hADMSC). We also observed that MF treatment increased the mitochondrial DNA and improved mitochondrial homeostasis by regulating mitofission-fusion plasticity via suppressing PINK1-PRKN-mediated mitophagy. Furthermore, MF treatment improved mitochondrial respiratory function by increasing mitochondrial oxygen consumption and expression of oxidative-phosphorylation (OXPHOS)-related proteins. Chemical-inhibition and gene knockdown experiments revealed that β3-AR-dependent PKA-p38 MAPK-CREB signalling is crucial for MF-mediated brown-fat formation via suppression of mitophagy in C3H10T1/2 MSCs.
CONCLUSIONS
MF promotes the brown adipocyte phenotype by suppressing mitophagy, which is regulated by PKA-p38MAPK-CREB signalling in C3H10T1/2 MSCs. Thus, we propose that MF may be a good browning inducer that can ameliorate obesity.
目的
来自芒果的芒果苷（MF）是一种类黄酮，已显示出对各种人类疾病（包括癌症，糖尿病和肥胖症）的治疗作用。尽管如此，MF 对褐色脂肪组织的非颤抖性产热及其潜在机制的影响仍不清楚。在这里，我们的目的是研究 MF 对棕色脂肪组织形成的影响及其在鼠 C3H10T1/2 间充质干细胞（MSC）中的分子机制。
材料/方法：为了确定 MF 对褐色脂肪组织形成的功能，用 MF 在脂肪生成分化鸡尾酒中处理鼠 C3H10T1/2 MSC，并通过 MF 介导的信号转导评估产热和相关代谢反应。分化人脂肪来源的 MSC 并用 MF 处理以确认其在产热诱导中的作用。
结果
MF 处理诱导了 UCP1 的表达，减少了 C3H10T1/2 MSC 中的甘油三酯（TG）。MF 还诱导了主要产热调节剂的表达：PGC1α、PRDM16 和 PPARγ，并上调了鼠 C3H10T1/2 MSC 和人脂肪来源间充质干细胞（hADMSC）中褐变标记物 CD137、HSPB7、TBX1 和 COX2 的表达。我们还观察到 MF 处理通过抑制 PINK1-PRKN 介导的线粒体自噬来增加线粒体 DNA 并改善线粒体稳态，从而调节线粒体裂变-融合可塑性。此外，MF 处理通过增加线粒体耗氧量和氧化磷酸化（OXPHOS）相关蛋白的表达来改善线粒体呼吸功能。化学抑制和基因敲低实验表明，β3-AR 依赖性 PKA-p38 MAPK-CREB 信号通路通过抑制 C3H10T1/2 MSC 中的线粒体自噬对于 MF 介导的褐色脂肪形成至关重要。
结论
MF 通过抑制线粒体自噬促进褐色脂肪细胞表型，这是通过 C3H10T1/2 MSC 中的 PKA-p38MAPK-CREB 信号通路调节的。因此，我们提出 MF 可能是一种良好的褐色脂肪诱导剂，可以改善肥胖症。
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