WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation.
WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation.
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DOI：
10.1016/j.cmet.2013.03.017
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发表时间：
2013-05-07
期刊：
影响因子：
29
通讯作者：
Long F
中科院分区：
文献类型：
--
作者：
Esen E;Chen J;Karner CM;Okunade AL;Patterson BW;Long F
WNT信号控制许多生物过程，包括后生动物的细胞分化。然而，WNT如何对细胞身份进行重新编程并不是很清楚。我们研究了细胞代谢在WNT诱导成骨细胞分化中的潜在作用。WNT3a通过增加关键糖酵解酶的水平来诱导被称为Warburg效应的有氧糖酵解。这种代谢调节需要LRP5，而不需要β-连环蛋白，并由RAC1下游的mTORC2-AKT信号介导。抑制WNT3a诱导的代谢酶在体外损害成骨细胞的分化。小鼠体内LRP5的缺失会减少出生后的骨量，降低骨细胞中mTORC2的活性和糖酵解酶，并降低血清乳酸水平。相反，表达导致骨量增加的突变LRP5的小鼠表现出骨中糖酵解的增加。因此，WNT-LRP5信号在一定程度上通过直接重新编程葡萄糖代谢来促进骨形成。此外，细胞代谢的调节可能代表了WNT蛋白广泛功能的一般机制。
WNT signaling controls many biological processes including cell differentiation in metazoans. However, how WNT reprograms cell identity is not well understood. We have investigated the potential role of cellular metabolism in WNT-induced osteoblast differentiation. WNT3A induces aerobic glycolysis known as Warburg effect by increasing the level of key glycolytic enzymes. The metabolic regulation requires LRP5 but not β-catenin, and is mediated by mTORC2-AKT signaling downstream of RAC1. Suppressing WNT3A-induced metabolic enzymes impairs osteoblast differentiation in vitro. Deletion of Lrp5 in the mouse, which decreases postnatal bone mass, reduces mTORC2 activity and glycolytic enzymes in bone cells and lowers serum lactate levels. Conversely, mice expressing a mutant Lrp5 that causes high bone mass exhibit increased glycolysis in bone. Thus, WNT-LRP5 signaling promotes bone formation in part through direct reprogramming of glucose metabolism. Moreover, regulation of cellular metabolism may represent a general mechanism contributing to the wide-ranging functions of WNT proteins.
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