Hypothalamic control of body weight: role of tri-iodothyronine (T3)

了解大脑控制能量摄入和消耗的方式，对改善动物生产和确定对抗人类肥胖的策略和疗法都有好处。在西伯利亚仓鼠身上研究这些过程提供了新的见解，因为它经历了春季和夏季脂肪沉积导致体重增加的年度周期，但随后通过降低食欲和燃烧脂肪储备度过了冬天。只需改变仓鼠生活的光周期，就可以在仓鼠身上诱导出这些相反的增重和减重状态。长白天导致夏季合成代谢状态，而短白天引起冬季分解代谢状态。这个项目的总体目标是了解哺乳动物的大脑如何建立这种分解代谢状态，从而导致长期的体重减轻。这个项目建立在我们之前的研究基础上，我们对肥胖和瘦仓鼠进行了比较，发现基因表达的变化仅限于下丘脑中的两个离散区域，这是大脑中已知在控制食物摄入和能量代谢方面很重要的区域。最重要的发现是，随着食欲下降和体重减轻时期的开始，编码将活跃的甲状腺激素(T3)转化为非活跃形式的酶的基因表达水平要高得多。这种酶只在下丘脑室系统内的细胞中发现，这种变化的后果是，在冬季分解代谢状态下，大脑中甲状腺激素的可获得性大幅减少。我们已经知道甲状腺激素在大脑中的可用性在功能上很重要，因为我们已经进行了试点实验，当甲状腺激素水平自然下降时，我们将少量活性甲状腺激素替换到暴露在短光周期中的金黄地鼠的下丘脑中。这种治疗方法能够阻止通常在短时间内发生的冬季体重下降。这个项目的目标是了解甲状腺激素在下丘脑中的作用，并准确地确定甲状腺激素可获得性的这种变化是如何带来的。该项目将通过使用自动监测系统来测量食物摄入量、体重和代谢率，并通过氧气消耗和二氧化碳产生来评估，从而准确地描述甲状腺激素的替代作用。然后，它将通过测量实验结束时从仓鼠脑组织中提取的部分基因的表达，找出其他哪些基因受到甲状腺激素替代的影响。甲状腺激素对大脑的初始发育很重要，在大脑中干细胞分裂形成神经元和支持细胞，因此我们将特别关注一组参与新神经元生成的基因。我们将找出冬季分解代谢状态的发展是否代表着成人大脑的一种“可塑性”变化。我们还将研究一组基因，这些基因参与维甲酸在大脑内的交流，维甲酸是一种维生素A的衍生物，因为我们已经在肥胖和瘦仓鼠身上检测到了这一信号通路的变化。一旦我们确定了受甲状腺激素影响的基因，我们将通过改变它们在实验仓鼠中的表达来测试它们的功能，然后确定它们在短日照下是否仍能表现出正常的代谢变化。我们将使用基因治疗技术，通过对病毒颗粒进行改造，将DNA携带到仓鼠的大脑中，然后将其整合和表达。这是一种安全的技术，因为病毒经过修改，不能复制感染其他组织。我们的初步研究表明，病毒介导的基因治疗可以产生下丘脑基因表达的长期变化，因此这是发现甲状腺激素调控基因功能的有效途径。

Understanding the ways that the brain controls energy intake and expenditure has benefits both for improved animal production and for identification of strategies and therapeutics to counteract obesity in man. Studying these processes in the Siberian hamster provides new insights because it undergoes an annual cycle of body weight gain due to fat deposition in spring and summer, but then survives winter by reducing its appetite and by burning its fat reserves. These opposing states of weight gain and loss can be induced in hamsters simply by changing the photoperiod in which the hamsters live. Long days induce the summer anabolic state whereas short days induce the winter catabolic state. The overall aim of this project is to understand how the mammalian brain can establish this catabolic state which results in long-term body weight loss. This project builds upon our previous studies which compared fat and lean hamsters and found changes in gene expression that were restricted to two discrete regions within the hypothalamus, the region of the brain known to be important in controlling food intake and energy metabolism. The most important finding is that the gene encoding the enzyme which converts active thyroid hormone (T3) into its inactive form is expressed at far higher levels as the period of decreased appetite and body weight loss begins. The enzyme is only found in cells lining the ventricular system in the hypothalamus, and the consequence of the change is that there is a massive reduction of the availability of thyroid hormone in the brain in the winter catabolic state. We already know that the availability of thyroid hormone in the brain is functionally important because we have conducted pilot experiments where we have replaced small amounts of active thyroid hormone into the hypothalamus in hamsters exposed to short photoperiods when levels naturally fall. This treatment was able to block all the winter body weight loss that usually occurs in short days. The objectives of this project are to understand how thyroid hormone acts within the hypothalamus, and to determine exactly how this change in thyroid hormone availability is brought about. The project will characterise exactly what replacement of thyroid hormone does, by measuring food intake, body weight and metabolic rate as assessed by oxygen consumption and carbon dioxide production using an automated monitoring system. It will then find out which other genes are affected by thyroid hormone replacement by measuring their expression in sections of brain taken from hamsters at the end of the experiment. Thyroid hormone is important for the initial development of the brain, where stem cells divide to form neurons and supporting cells, so we will pay particular attention to a group of genes which are involved in the generation of new neurons. We will find out if the development of the winter catabolic state represents a 'plastic' change in the adult brain. We will also look at a group of genes that are involved in communication within the brain by retinoic acid, a vitamin A derivative because we have already detected changes in this signalling pathway in fat and lean hamsters. Once we have identified genes that are affected by thyroid hormone, we will test their function by altering their expression in experimental hamsters, and then determining whether they can still show the normal metabolic changes when exposed to short days. We will use the technique of gene therapy whereby viral particles are modified to carry DNA into the hamster's brain, and this will then be incorporated and expressed. This is a safe technique because the viruses are modified so that they cannot replicate to infect other tissue. Our preliminary studies show that virally-mediated gene therapy can produce long-term changes in hypothalamic gene expression, so this is an effective way to discover the function of those genes which are regulated by thyroid hormone.