摘要
睫状神经营养因子(CNTF)是一个天然产生的分子量大约为22kD的蛋白，属于白介素-6细胞因子家族。应用CNTF可引起动物的食欲下降和体重减轻，在遗传肥胖型小鼠(ob／ob，db／db)中CNTF可引起脂肪的优先减少。尤其引人注目的是，CNTF可纠正饮食诱导型的小鼠肥胖(DIO)，这种类型的肥胖在人类中分布最广。因此，CNTF作为一种很有潜力的治疗肥胖症的药物而受到重视，但对其减肥机制的研究尚不够深入。
肥胖的形成是一个复杂的过程，涉及多个系统、多种途径和多种细胞因子，但从生理学的角度讲，它是由于能量摄入与能量支出失衡造成的。因此，本论文的主要目标是从分子水平上研究CNTF对能量摄入和能量支出的影响，从而探讨CNTF调节能量平衡的相关作用机制。
在能量支出方面，本论文选用小鼠棕色脂肪组织和骨骼肌(腓肠肌)为目标组织，用western blotting和RT-PCR的方法，从蛋白水平和mRNA水平来检测CNTF对这两个组织上的解偶联蛋白UCP1、UCP2和UCP3表达的影响。解偶联蛋白(UCP_s)是一类线粒体内膜蛋白，质子可通过其渗漏回基质，从而使氧化磷酸化和ATP的合成解偶联，能量遂以热量的形式散发掉。目前在哺乳动物中发现的解偶联蛋白主要有三种：UCP1、UCP2和UCP3。UCPI主要分布在棕色脂肪组织，UCP2分布广泛，UCP3主要分布在骨骼肌组织和棕色脂肪组织。棕色脂肪组织是啮齿类动物产热的主要位置。人类成年后棕色脂肪含量很少，而骨骼肌含量却很大。本研究先通过饲养实验考察CNTF对小鼠体重、摄食量和血糖的影响，从而确定CNTF的给药剂量。接下来western blotting实验的结果表明，CNTF腹腔给药6天实验组棕色脂肪组织UCP1蛋白水平与盐水处理组相比有明显增加(P＜0.01)。RT-PCR实验的结果表明，CNTF外周急性给药(处理1小时)对棕色脂肪组织中UCP1、UCP2和UCP3的mRNA水平没有影响，但对腓肠肌UCP3的表达有上调作用(P＜0.05)；持续给药3天，对棕色脂肪组织中UCP1以及腓肠肌UCP3的表达有上调作用(P＜0.05)，但对棕色脂肪组织UCP2和UCP3的mRNA水平没有影响。这些实验结果表明，CNTF持续给药可以通过UCP1来诱导棕色脂肪组织产热；UCP2和UCP3对CNTF诱导的棕色脂肪的产热没有贡献；而无论急性或持续给药，CNTF都可以通过UCP3来诱导腓肠肌产热；类似实验结果尚未见报道。
在能量摄入方面，本实验采用微透析和放射免疫相结合的方法，检测大鼠下丘脑室旁核(PVN)神经肽Y(NPY)含量的动态变化，以评估CNTF对下丘脑NPY分泌的影响。近年的研究认为下丘脑是调节食欲和能量平衡的重要脑区，其中由抑制摄食和刺激摄食的神经肽组成的网络发挥着重要调控作用。在这些神经肽中，NPY是已知的最有效的中枢食欲刺激物，向下丘脑相关区域注射NPY会引起强烈的摄食反应；当机体处于饥饿等负能量平衡状态中时，弓状核(ARC)中NPY表达水平上升，ARC和PVN等NPY释放位点的NPY水平增加，机体启动合适的行为(摄食增加)和代谢反应以恢复能量平衡。本实验的研究结果表明，CNTF侧脑室给药导致室旁核透析液中NPY含量的迅速下降，30分钟时降幅达到53％(P＜0.01)；随后透析液中NPY的水平缓慢上升，60、90、120分钟时分别为基线水平的58％、78％和85％(P＜0.05)；150分钟后，NPY水平恢复到基线水平(P＞0.05)。本研究结果证明CNTF可直接影响下丘脑NPY分泌。
综上所述，本研究发现CNTF可以诱导骨骼肌产热；CNTF诱导的棕色脂肪的产热中，只有UCP1有贡献，UCP2和UCP3对CNTF没有响应；CNTF可降低室旁核NPY的分泌。这些结果从分子水平揭示了CNTF调节能量平衡的相关机制，也为减肥药物的筛选方向和筛选平台的建立提供了新的思路。
Ciliary neurotrophic factor (CNTF) is a member of the cytokine family structurally related to leukemia inhibitory factor, IL-6 and other cytokines. Administration of CNTF can suppresses appetite and cause weight loss in animals just like leptin. It is found that CNTF can cause preferential loss of fat in genetically obese mice (ob/ob, db/db). Especially, CNTF is also effective in diet-induced obesity mice that are more representative of human obesity, and which are resistant to leptin. In this study, we investigated the related mechanism of CNTF regulating energy balance from energy expenditure and energy intake.
Enhancing energy expenditure is an important way to loss weight. Recent years, uncoupling proteins (UCPs), expressed on the inner mitochondrial membrane, are thought to play a major role in energy expenditure. UCPs serve to uncouple respirations with ATP synthesis in mitochondrial. Accordingly, energy is wasted as heat. Three major uncoupling proteins have been identified in mammals—UCP1, exclusively in brown adipose tissue (BAT); UCP2, expressed ubiquitously; UCP3, predominantly in muscle and BAT. BAT is recognized as the primary site of thermogenesis in rodents, but adult humans, unlike rodents, do not have large, distinct depots of brown adipose, tissue. Skeletal muscle, on the other hand, represents up to 40% of total body weight and is endowed with significant mitochondrial capacity, causing many researchers to investigate its contribution to adaptive thermogenesis.
Therefore, in our study we sought to assess whether CNTF could increase energy expenditure through enhancing UCPs level in mice BAT and gastrocnemius muscle. The results from western blotting showed that CNTF systemic administration increased mice UCP1 level of interscapular BAT. The UCP1 protein level of normal mice, intraperitoneally injected with CNTF (0.2μg/g/day) for 6 days, was more than twice that of saline-treated mice (230% vs control, P＜0.01). The results from RT-PCR showed that CNTF acute treatment had no effects on the expression of UCPs in BAT, but it increased the expression of UCP3 in gastrocnemius (156% vs control, P＜0.05). Intraperitoneal injection of 0.2mg/kg CNTF for 3 days elevated the expression of UCP1 in BAT (153% vs control, P＜0.05) and UCP3 in gastrocnemius (154% vs control, P＜0.05), but the mRNA level of UCP2 and UCP3 in BAT was not affected. These results suggestd CNTF increased thermogenic activity in gastrocnemius muscle by UCP3 and brown adipose tissue only by UCP1.
As to energy intake, cumulative evidences show that a hypothalamic circuitry comprising of a number of orexigenic and anorectic neuropeptides is critical for food intake. Among this signals, neuropeptide Y (NPY) is the prime candidate to stimulate feeding. NPY is produced in the arcuate nucleus (ARC) and released in the paraventricular nucleus (PVN) and adjoining neural sites of the hypothalamus. A ligand-specific subunit of CNTF receptor complex (CNTFRα) has also been demonstrated expression in ARC and PVN.
In this study we used radioimmunoassay-microdialysis procedure to measure the extracellular level of neuropeptide Y (NPY) in paraventricular nucleus (PVN) so that we could assess the effect of CNTF on secrete of NPY. The results showed NPY concentrations in PVN of freely moving rats rapidly decreased to the lowest point, 47% (P＜0.01) of basal level, in 30 minutes after intracerebroventricular injection 5μg CNTF, and then increased slowly to 58% (P＜0.05), 78% (P＜0.05) and 85% (P＜0.05) of basal level respectively at 60, 90 and 120 rain. It became no significant difference with basal level at 150 and 180 rain (P＞0.05). This result was the direct evidence to illustrate CNTF could decrease NPY peptide level in PVN of freely moving rats.
In the present study, firstly, we found that CNTF elevated the expression of UCP1 in BAT and UCP3 in gastrocnemius muscle. Secondly, our data also showed that direct evidence to illustrate CNTF could decrease extracellular NPY level in hypothalamus. These were contributed for developing the mechanism of CNTF to lose weight.
引文
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