Retinoic acid signalling within the hypothalamus is essential to the photoperiodic neuroendocrine response

所有动物都通过食物消耗和能量消耗的精细平衡来严格控制体重;你在野外看不到肥胖的动物。决定这种平衡的大脑区域被称为下丘脑，它是控制食物摄入和代谢的指挥中心。研究这个系统的理想动物模型是那些经历季节变化的动物，当白天长度缩短时（进入冬季）体重增加，当白天长度增加时（进入夏季）体重减轻;通过改变日光暴露的小时数，下丘脑可以切换到命令体重增加或体重减轻，并且可以研究和理解控制这种切换的机制。最近和新出现的工作已经开始阐明这些机制，正在产生许多惊喜。甲状腺激素通常由甲状腺产生，并且以其对代谢率的影响而闻名。然而，在大脑中，酶能够将甲状腺激素转化为其生物活性形式并再次转化。白天的长度（光暗周期的长度）控制着下丘脑内甲状腺激素的局部产生，这反过来又对体重和繁殖的季节性控制很重要。我们现在已经在下丘脑中发现了一个全新的控制系统，它来自我们饮食中的一个重要组成部分，维生素A。这种维生素被转化为一种名为视黄酸的基因表达的有效控制开关，其作用方式与甲状腺激素相似。与甲状腺激素一样，视黄酸可以通过适当的酶在大脑的下丘脑内局部产生，然后可以通过激活靶基因的专门受体进行运输和检测。白天的长度再次决定了视黄酸通过改变视黄酸的产生和敏感性状态来控制大脑中这些基因的能力。在动物中，在夏季白天的长度，动物似乎使视黄酸和受体是敏感的，而那些暴露在冬季白天长度似乎使较少的视黄酸和受体是不敏感的。这个项目将研究复杂的机制，这种视黄酸控制开关的基础，并确定如何可以操纵它来控制体重。我们的目标是确定大脑对视黄酸的反应性在何处、何时以及如何变化，我们将在对日照长度变化做出反应的动物（大鼠）中进行这项研究。我们还将测试大脑是否在某些条件下产生更多的视黄酸相对于其他条件（即夏季与冬季白天长度）。该项目的一个重要目的是了解功能步骤的顺序，通过这些步骤，白天的长度可以改变大脑中的视黄酸信号，反过来，我们希望确定视黄酸如何改变CNS水平的食物摄入和生长方面的生理状态。由于认识到维生素A缺乏是世界许多地区的一个主要营养问题，在控制下丘脑功能的下丘脑中意外发现一种全新的信号机制显然具有全球相关性和重要性。操纵视黄酸信号通路以影响食物消耗和肥胖的潜力可能提供一些新的治疗机会。

All animals keep tight control of their body weight through a fine balance of food consumption and energy expenditure; you do not see fat animals in the wild. The region of the brain determining this balance is called the hypothalamus, the command centre that controls food intake and the metabolism that burns this off. Ideal animal models to study this system are those that undergo seasonal change, gaining weight when day length shortens (heading into winter) and losing weight when day length increases (heading into summer); by altering the number of hours of daylight exposure the hypothalamus can be switched to command either weight gain or weight loss and the mechanisms that control this switch can be studied and understood. Recent and emerging work which has begun to shed light on these mechanisms is generating many surprises. Thyroid hormone is normally produced by the thyroid gland and it is known for its effects on metabolic rate. However within the brain enzymes are able to convert thyroid hormone into its bioactive form and back again. Day length (the length of the light-dark cycle) controls the local production of thyroid hormone within the hypothalamus and this in turn is important to seasonal control of body weight and reproduction. We have now discovered an entirely new system of control in the hypothalamus that derives from an essential part of our diet, vitamin A. This vitamin is converted to a potent control switch of gene expression called retinoic acid that acts in a similar way to thyroid hormone. Also like thyroid hormone, retinoic acid can be produced locally within the hypothalamus of the brain, via the appropriate enzyme, and it can then be transported and detected by specialised receptors that activate target genes. Once again day length determines the ability of retinoic acid to control these genes in the brain by changing the production and state of sensitivity to retinoic acid. In animals on summer day length, the animals appear to make retinoic acid and receptors are sensitive to it, while those exposed to a winter day length appear to make less retinoic acid and receptors are less sensitive to it. This project will study the sophisticated mechanisms that underlie this retinoic acid controlled switch and determine how it may be manipulated to control body weight. We aim to identify where, when and how the brain changes in its responsiveness to retinoic acid and we will do this in animals (rats) that respond to changes in day length. We will also test whether the brain produces more retinoic acid in some conditions relative to others (ie summer versus winter day length). An important aim of this project is to understand the sequence of functional steps by which day length can alter retinoic acid signals within the brain and in turn we want to identify how retinoic acid then alters physiological status in terms of food intake and growth at a CNS level. Given the recognition that vitamin A deficiency is a major nutritional problem in many parts of the world, the unexpected discovery of an entirely new signalling mechanism in the hypothalamus, which controls hypothalamic function is clearly of global relevance and importance. The potential of manipulating the retinoic acid signalling pathway to influence food consumption and obesity may offer some novel therapeutic opportunities.