Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms.
Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms.
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二甲双胍通过依赖于5'-腺苷酸活化蛋白激酶（AMPK）和不依赖于AMPK的两种机制抑制脂肪生成。
DOI：
10.1016/j.mce.2016.11.011
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发表时间：
2017-01-15
影响因子：
4.1
通讯作者：
Yarwood SJ
中科院分区：
文献类型：
--
作者：
Chen SC;Brooks R;Houskeeper J;Bremner SK;Dunlop J;Viollet B;Logan PJ;Salt IP;Ahmed SF;Yarwood SJ
由于骨髓间充质干细胞(MSC)分化的改变，2型糖尿病(T2 DM)患者的骨密度降低，骨折风险增加。这导致分化的平衡从骨形成(成骨)转向脂肪细胞发育(脂肪生成)。常用的抗糖尿病药物二甲双胍激活成骨转录因子Runx2(Runx2)，该转录因子可能抑制脂肪生成，从而改善骨骼健康。在这里，我们研究代谢酶，AMP激活的蛋白激酶(AMPK)，在二甲双胍的这些保护作用中的参与。在多能C3H10T1/2MSCs中观察到二甲双胍的抗成脂作用，在该细胞中，二甲双胍通过相互调控Runx2和成脂转录因子PPARγ的活性而抑制成脂。这些效应似乎不依赖于AMPK的激活，而是通过抑制mTOR/p70S6K信号通路实现的。基础的AMPK和mTOR/p70S6K活性似乎确实是脂肪形成所必需的，正如AMPK抑制剂化合物C的使用所证明的那样，这一观察结果进一步得到了AMPK基因敲除小鼠胚胎成纤维细胞(MEF)的支持，在MEF中，通过减少脂肪积累和脂肪生成转录因子C/EBPβ的表达来评估脂肪形成，发现对AMPK是绝对需要的。在野生型MEF中，使用二甲双胍或AMPK特异性激活剂A769662进一步激活AMPK，也与抑制脂肪生成有关。因此，基础的AMPK活性似乎是脂肪生成所必需的，二甲双胍可以通过AMPK依赖或独立的机制抑制脂肪生成，这取决于细胞环境。二甲双胍可通过AMPK依赖或非依赖机制抑制脂肪生成，具体取决于细胞环境。二甲双胍抑制C3H10T1/2间充质干细胞(MSCs)的成脂作用，其作用不依赖AMPK。二甲双胍对骨髓间充质干细胞中的成骨(Runx2)和成脂(PPAR)转录因子(γ)起相互调控作用。基础AMPK和mTOR/p70S6K活性是MSCs成脂所必需的。
People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context. Metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context. Metformin suppresses adipogenesis in C3H10T1/2 mesenchymal stem cells (MSCs), independently of AMPK. Metformin exerts reciprocal control over osteogenic (Runx2) and adipogenic (PPARγ) transcription factors in MSCs. Basal AMPK and mTOR/p70S6K activity are required for adipogenesis in MSCs.