抵抗素下游信号通路与脂源性NPY的交互作用和分子调控网络

Adipose tissue has been recognized as a largest endocrine organ secreting a variety of signaling molecules called adipokines. These adipokines play key roles in regulating energy homeostasis, lipid metabolism, immunity, and other physiological functions. Neuropeptide Y (NPY) is a 36-amino-acid peptide involved in the regulation of metabolic homeostasis. NPY is mainly synthesized in the central and peripheral nervous systems. The neuron-derived NPY plays important roles in obesity, metabolic syndrome, atherosclerosis and other diseases. Recently, it was suggested that circulating NPY comes from adipose tissue. Adipocyte-derived NPY promotes pre-adipocytes proliferation via Y1 receptor. Nevertheless, the regulation, secretory pathways and potential endocine effects of NPY in adipose tissue are poorly elucidated. We have firstly found adipocyte-derived NPY involved in the downstream signal pathways of resistin. In follow-up study, we will focus on the relation between downstream pathways of resistin and adipocyte-derived NPY at the single cell level using new developed single cell real-time fluorescence detection system and total internal reflection fluorescence microscopy combined with the Transwell indirect-contact coculture system. Taken together, our work will deepen the understanding of complex metabolic network. It will provide new drug targets for the treatment of obesity, metabolic syndrome and other diseases.

脂肪组织目前被认为是机体最大的内分泌器官。脂肪细胞整合多方面的信号分泌多种脂肪因子调节机体的多项生理功能。神经肽Y（NPY）是一个含有36个氨基酸的多肽。过去的研究认为NPY主要在神经系统表达。神经源性NPY参与调节机体代谢，在肥胖、代谢综合症、动脉粥样硬化等发生发展中起着重要作用。近来研究发现血液中NPY可能主要来源于脂肪细胞，脂源性NPY通过Y1受体促进前脂细胞的增殖。然而脂源性NPY的作用、分泌机制、信号通路及调控均不清楚。我们在承担的青年基金中首次发现脂源性NPY参与抵抗素的下游信号通路。在后续研究中拟运用新发展的观测单分子荧光的全内反射荧光显微成像和单细胞实时荧光检测系统结合共培养体系，在单细胞水平研究抵抗素下游信号与脂源性NPY的交互作用及调控。其研究将深化我们对于脂肪细胞及分泌的多种信号分子构成的复杂代谢网络的认识。为肥胖、代谢综合症等疾病的治疗提供新的临床方向。

肥胖及其并发症已成为一个世界性的健康问题。脂肪细胞作为关键节点通过分子网络调控肥胖及其并发症的病理生理过程，并且其调控网络呈现随时空动态变化的特点。本课题采用了全内反射荧光显微成像和单细胞实时荧光检测系统等监测了脂肪细胞中NPY和抵抗素的分子事件结合质谱以及共培养体系探索其分子网络的一些动态变化；观察了脂肪细胞间以及与其他细胞的通讯和交互，通过生物信息学方法凝炼出分子网络中的重要调控节点，RNA干扰对候选靶点进一步功能验证。我们发现脂源性NPY是一种新的涉及到复杂分子网络调控的脂肪因子。它受到包括抵抗素在内的多方高度调控和影响。此外，脂源性NPY通过VDAC2相关的凋亡途径作用于血管内皮。本项目不仅深化了我们对于单个及脂肪细胞群的认识。更为肥胖及其并发症的防治提供了新的药物靶点和思路。