间歇性低氧诱导的脂肪组织炎症通过TRPV4钙通道抑制脂肪分解和产热效应的机制研究

阻塞性睡眠呼吸暂停(OSA)通常合并脂肪代谢紊乱，脂肪组织中巨噬细胞导致的慢性炎症可能是其致病机制之一，但OSA中引起脂肪代谢紊乱的具体机制并不清楚。瞬时受体电位香草型(TRPV)钙通道是炎症调节脂肪代谢的重要蛋白通道。前期研究发现间歇性低氧动物模型中，白色脂肪组织的原始巨噬细胞促进炎症极化标记物及TRPV4钙通道高表达；体外间歇性低氧能够激活巨噬细胞的炎症通路和促使共培养脂肪细胞的钙内流，而TRPV4钙通道的激动剂能够抑制去甲肾上腺素(NE)对脂肪细胞的分解和产热基因的促表达。于是，我们提出假说：间歇性低氧能够启动脂肪组织中巨噬细胞的炎症反应，相关炎症通过激活TRPV4钙通道逆转NE的脂肪分解和产热效应，最终导致肥胖的发生。本项目采用间歇性低氧动物模型与多种免疫学技术，拟在间歇性低氧-免疫细胞-脂肪细胞的分子网络中，进一步明确OSA中脂肪炎症导致脂肪代谢紊乱的具体机制。

Obstructive sleep apnea (OSA) is often associated with adipose metabolic dysfunction, adipose tissue inflammation is one of the common and important pathological mechanisms of OSA, however, the mechanism which causes abnormal adipose metabolism in OSA is not clear. Transient receptor potential vanilloid (TRPV) calcium channel as a common mediator for the molecular and physiological programs are connected at levels to regulate the adipose metabolism. Our preliminary data revealed that the pro-inflammatory polarization markers of adipose tissue macrophages and TRPV4 subtype in white adipose tissue were highly expressed in the intermittent hypoxia animal model. In vitro, intermittent hypoxia condition could stimulate the activation of the macrophage inflammatory pathway and the calcium influx in the co-cultured adipocyte; and TRPV4 agonist could inhibit the stimulation of norepinephrine (NE) on both lipolysis and thermogenesis. Therefore, we proposed a hypothesis: intermittent hypoxia in OSA could promote the occurrence of adipose tissue inflammation, and the related inflammation could reverse the effect of NE on adipocyte lipolysis and thermogenesis through the TRPV4 calcium channel, and finally lead to the occurrence of obesity. This project is expected using the intermittent hypoxia animal model and many immunology techniques to clarify the network of immune cells in adipose tissue and adipocytes as well as immune molecules and to inquire the exact mechanism that the effect of adipose tissue inflammation on adipose metabolic dysfunction in OSA.