Central adiponectin induces trabecular bone mass partly through epigenetic downregulation of cannabinoid receptor CB1
Central adiponectin induces trabecular bone mass partly through epigenetic downregulation of cannabinoid receptor CB1
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中枢脂联素部分通过大麻素受体 CB1 的表观遗传下调诱导小梁骨量
DOI：
10.1002/jcp.27460
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Chen, Jake
中科院分区：
文献类型：
--
作者：
Jiang, Hua;Wu, Yuwei;Chen, Jake
球状或全长形式的中枢脂联素（APN）通过下丘脑降低交感神经张力并增加小鼠骨小梁质量。已知大麻素1型（CB 1）受体在下丘脑腹内侧核中表达，并通过控制交感神经活性参与能量代谢。然而，中枢APN是否可以通过CB 1受体影响内源性大麻素信号通路来调节骨代谢尚未被表征。在这里，我们证明，gAPN下调CB 1在胚胎小鼠下丘脑N1细胞在体外的表达。gAPN脑室内（icv）输注也降低APN敲除（APN-KO）和野生型小鼠中下丘脑CB 1表达和骨形成参数。最重要的是，用CB 1受体激动剂花生四烯酸-2 '-氯乙胺或拮抗剂利莫那班分别icv输注预处理的小鼠减弱或增强了骨形成的中枢APN诱导。然后，我们研究了表观遗传信号转导机制是否参与gAPN下调下丘脑CB 1表达。我们发现gAPN增强了各种组蛋白脱乙酰酶（HDAC）的表达水平，尤其是HDAC 5。此外，染色质免疫沉淀分析显示HDAC 5结合到CB 1启动子的转录起始位点转录起始位点2区域。总之，我们的研究确定了一种可能的新的中央APN-HDAC 5-CB 1信号传导机制，通过下丘脑CB 1表达的表观遗传调节促进外周骨形成。
Central adiponectin (APN) in either the globular (gAPN) or full-length forms decreases sympathetic tone and increases trabecular bone mass in mice through the hypothalamus. It is known that cannabinoid type-1 (CB1) receptors are expressed in the hypothalamic ventromedial nucleus and participate in energy metabolism by controlling sympathetic activity. However, whether central APN could influence endocannabinoid signaling through CB1 receptor to regulate bone metabolism has not been characterized. Here we demonstrate that gAPN downregulated CB1 expression in embryonic mouse hypothalamus N1 cells in vitro. gAPN intracerebroventricular (icv) infusions also decreased hypothalamic CB1 expression and bone formation parameters in APN-knockout (APN-KO) and wild-type mice. Most importantly, mice pretreated with icv infusions with the CB1 receptor agonist arachidonyl-2 '-chloroethylamine or antagonist rimonabant attenuated or enhanced respectively central APN induction of bone formation. We then investigated whether epigenetic signaling mechanisms were involved in the downregulation of hypothalamic CB1 expression by gAPN. We found gAPN enhanced expression levels of various histone deacetylases (HDACs), especially HDAC5. Furthermore, chromatin immunoprecipitation assays revealed HDAC5 bound to the transcriptional start site transcription start site 2 region of the CB1 promoter. In summary, our study identified a possible novel central APN-HDAC5-CB1 signaling mechanism that promotes peripheral bone formation through epigenetic regulation of hypothalamic CB1 expression.