下丘脑腹内侧核COUP-TFII基因在能量动态平衡中的作用

Food intake and energy expenditure, the key components of the energy homeostasis system, are tightly modulated by the center nervous system (CNS), especially by the ventromedial hypothalamic nucleus (VMH). Nonetheless, the molecular mechanisms how the VMH neurons participate in the regulation of the food intake and energy expenditure are still largely unclear. It has been demonstrated that COUP-TFII gene is involved in the metabolic regulation in the adipocyte tissue. Our unpublished data show that COUP-TFII gene might also regulate the energy homeostasis in the CNS, and we observed that COUP-TFII gene is preferentially expressed in the murine developing and mature VMH neurons. However, little is known about its function in the VMH nucleus. In the study, we will generate both the VMH specific conditional knockout mutant and overexpressing mutant mice of COUP-TFII gene. We are planning to investigate how COUP-TFII gene regulates the food intake and energy expenditure in the VHM nucleus, which VHM neuronal signaling pathway might be controlled by the gene, and how the VMH neuronal signals and adipocyte signals are coordinated to modulate the energy balance. Thus, our proposed study will benefit not only the understanding of the molecular mechanisms of the energy homeostasis regulation in CNS, but also the understanding of the etiology and therapy of obesity.

食物摄取和能量消耗是机体能量动态平衡的决定因素，受中枢神经系统（尤其是下丘脑腹内侧神经核，VMH）精细调控。然而，有关VMH核参与食物摄取和能量消耗的机理仍不清楚。申请人原实验室研究表明，COUP-TFII基因在脂肪组织参与代谢调控；申请人发现，COUP-TFII基因亦可能在中枢神经系统调控能量动态平衡，而且COUP-TFII基因特异性地在VMH神经核高表达。但是，COUP-TFII基因在VMH核的功能及作用机理尚待研究。本项目应用VMH核条件性COUP-TFII基因剔除或过表达小鼠模型，研究COUP-TFII基因如何调控食物摄取和能量消耗，解析COUP-TFII基因调控的VMH神经元通路，及VMH核神经信号与脂肪组织信号的相互作用。本项目对阐明VMH神经核对机体内部能量动态平衡的调控机制有重要理论意义，为探索肥胖症的治疗途径提供理论依据。

下丘脑的多个神经核团如腹内侧核、室旁核、弓状核等在调控机体能量动态平衡与胚胎发育中发挥重要的功能；然而，介导下丘脑核团发育与其功能的细胞分子机制还不清楚。COUP-TFII基因编码一个核受体蛋白。临床研究发现，COUP-TFII基因突变导致胎儿发育迟缓、先天性膈疝和先天性心脏病等病症；至今，COUP-TFII基因突变引起发育迟缓的机理尚未知。在本项目中，我们首先发现，COUP-TFII基因在小鼠早期发育的下丘脑中表达。我们获得腹侧端脑特异的COUP-TFII基因条件性敲除小鼠，观察到突变小鼠生长发育迟缓。进一步研究发现，Brn2阳性神经元的凋亡增加与异常迁移导致突变小鼠的下丘脑室旁核发育异常；而且，突变小鼠垂体前叶有不正常的血细胞团，垂体后叶萎缩。显然，COUP-TFII基因突变小鼠下丘脑--垂体内分泌轴形成异常。分子机制研究显示，Bdnf和Nrp1基因的表达在突变小鼠胚胎脑区下调；免疫共沉淀-定量qPCR结果表明，Bdnf基因是COUP-TFII基因的直接下游靶基因。我们最新的研究结果证实，COUP-TFII基因通过促进Bdnf和Nrp1等基因的表达，保证下丘脑-垂体内分泌轴尤其是下丘脑室旁核正常形成，进而防止胚胎生长发育迟缓。本项目对阐明下丘脑发育与功能机制有重要理论意义，揭示了临床生长发育迟缓的新机理。