T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/β-Catenin Pathway
T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/β-Catenin Pathway
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T 细胞因子 7 (TCF7)/TCF1 反馈控制棕色脂肪细胞中的骨钙素信号传导，与 Wnt/β-连环蛋白途径无关
DOI：
10.1128/mcb.00562-17
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发表时间：
2018-04-01
影响因子：
5.3
通讯作者：
Gan, Xiaoqing
中科院分区：
文献类型：
--
作者：
Li, Qian;Hua, Yue;Gan, Xiaoqing
骨钙素最近被证明通过多个途径调节能量平衡。脂肪组织是能量代谢的主要器官，在小鼠体内注射重组骨钙素可以促进能量消耗，从而对抗肥胖和糖耐量异常。骨钙素在胰岛β细胞中的调节已经有了很好的文献记载；然而，骨钙素是否也能作用于脂肪细胞，如果是的话，它是如何发挥作用的，还不清楚。在这里，我们提供了证据来证明骨钙素在棕色脂肪细胞产热中的特定作用。重要的是，编码G蛋白偶联受体的Gprc6a基因作为骨钙素受体的表达被棕色脂肪样分化所激活。骨钙素可进一步增强Gprc6a的表达。同时，过表达和敲除实验证实了Gprc6a在骨钙素介导的致热基因激活中的关键作用。我们首次将Tcf7和Wnt3a确定为骨钙素信号转导的可能靶点。T细胞因子7(Tcf7)属于Tcf/LEF1家族的DNA结合因子，对典型的WNT/β-catenin途径至关重要；然而，Tcf7调节Gprc6a和Ucp1启动子的激活不依赖于β-catenin。进一步的研究表明，Tcf7的活性可能需要生热辅活化子PRDM16和组蛋白去甲基酶LSD1。因此，我们的研究描述了棕色脂肪细胞生理中骨钙素-GPRC6A轴的Tcf7依赖的反馈控制。
Osteocalcin has recently been shown to regulate energy homeostasis through multiple pathways. Adipose tissue is a main organ of energy metabolism, and administration of recombinant osteocalcin in mice promoted energy consumption, thus counteracting obesity and glucose intolerance. The regulation of osteocalcin in islet beta cells has been well documented; however, it is unknown whether osteocalcin can also act on adipocytes and, if it does, how it functions. Here, we provide evidence to demonstrate a specific role for osteocalcin in brown adipocyte thermogenesis. Importantly, expression of the Gprc6a gene encoding a G protein-coupled receptor as an osteocalcin receptor was activated by brown fat-like differentiation. Moreover, Gprc6a expression could be further potentiated by osteocalcin. Meanwhile, overexpression and knockdown experiments validated the crucial role of Gprc6a in osteocalcin-mediated activation of thermogenic genes. For the first time, we identified Tcf7 and Wnt3a as putative targets for osteocalcin signaling. T cell factor 7 (TCF7) belongs to the TCF/LEF1 family of DNA binding factors crucial for the canonical WNT/beta-catenin pathway; however, TCF7 modulates Gprc6a and Ucp1 promoter activation independent of beta-catenin. Further studies revealed that the thermogenesis coactivator PRDM16 and the histone demethylase LSD1 might be required for TCF7 activity. Hence, our study described a TCF7-dependent feedback control of the osteocalcin-GPRC6A axis in brown adipocyte physiologies.