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提高动物产量和确定对抗人类肥胖的策略和治疗方法都有好处。在西伯利亚仓鼠身上研究这些过程提供了新的见解，因为它在春季和夏季由于脂肪沉积而经历了每年一次的体重增加周期，但随后通过减少食欲和燃烧脂肪储备来度过冬季。这些相反的体重增加和减少的状态可以通过改变仓鼠生活的光周期来诱导。长昼诱导夏季合成代谢状态，短昼诱导冬季分解代谢状态。这个项目的总体目标是了解哺乳动物的大脑是如何建立这种导致长期体重减轻的分解代谢状态的。这个项目建立在我们之前的研究基础上，该研究比较了肥胖和瘦弱的仓鼠，发现基因表达的变化仅限于下丘脑的两个独立区域，下丘脑是大脑中控制食物摄入和能量代谢的重要区域。最重要的发现是，当食欲下降和体重减轻的时期开始时，编码将活性甲状腺激素（T3）转化为非活性形式的酶的基因的表达水平要高得多。这种酶只存在于下丘脑脑室系统的细胞中，这种变化的结果是，在冬季分解代谢状态下，大脑中甲状腺激素的可用性大幅减少。我们已经知道，甲状腺激素在大脑中的可用性在功能上是重要的，因为我们已经进行了试点实验，我们在仓鼠暴露于短光周期时将少量活跃的甲状腺激素替换为下丘脑，当水平自然下降时。这种治疗方法能够阻止通常在短时间内发生的所有冬季体重减轻。该项目的目的是了解甲状腺激素在下丘脑中的作用，并确定甲状腺激素可用性的这种变化是如何产生的。该项目将通过测量食物摄入量、体重和代谢率来准确描述甲状腺激素替代的作用，并使用自动监测系统通过耗氧量和二氧化碳产量来评估代谢率。然后，在实验结束时，它将通过测量从仓鼠大脑中提取的部分甲状腺激素的表达，找出哪些其他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，所以我们将特别关注一组参与新神经元生成的基因。我们将发现冬季分解代谢状态的发展是否代表了成人大脑的“可塑性”变化。我们还将研究一组基因，这些基因通过维甲酸（维生素a的衍生物）参与大脑内的交流，因为我们已经在肥胖和瘦弱的仓鼠中发现了这种信号通路的变化。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，然后确定它们在暴露于短时间内是否仍能显示正常的代谢变化。我们将使用基因治疗技术，将病毒颗粒进行修饰，使其携带DNA进入仓鼠的大脑，然后将其整合并表达。这是一种安全的技术，因为病毒经过修饰，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引起下丘脑基因表达的长期变化，因此这是发现受甲状腺激素调节的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.