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微妙平衡来严格控制自己的体重；你在野外看不到肥胖的动物。大脑中决定这种平衡的区域被称为下丘脑，它是控制食物摄入量和新陈代谢的指挥中心，负责燃烧食物。研究这一系统的理想动物模型是那些经历季节性变化的动物，当白天长度缩短(进入冬季)时体重增加，当白天长度增加(进入夏季)时体重下降；通过改变日光暴露的小时数，下丘脑可以切换到控制体重增加或减轻，控制这种切换的机制可以被研究和理解。最近和正在开展的工作已经开始阐明这些机制，并产生了许多令人惊讶的结果。甲状腺激素通常由甲状腺产生，它对代谢率的影响是众所周知的。然而，在大脑中，酶能够将甲状腺激素转化为具有生物活性的形式，然后再转化回来。白天的长度(光-暗周期的长度)控制着下丘脑中甲状腺激素的局部产生，这反过来对季节性控制体重和繁殖很重要。我们现在已经在下丘脑中发现了一种全新的控制系统，它来自我们饮食中必不可少的维生素A。这种维生素被转化为一种强大的基因表达控制开关，称为维甲酸，其作用方式类似于甲状腺激素。与甲状腺激素一样，维甲酸也可以通过适当的酶在大脑的下丘脑局部产生，然后通过激活目标基因的特殊受体进行运输和检测。一天的长度再次决定了维甲酸通过改变对维甲酸的产生和敏感状态来控制大脑中这些基因的能力。在夏天白天的动物中，这些动物似乎产生维甲酸，受体对它敏感，而那些暴露在冬季白天的动物似乎产生更少的维甲酸，受体对它不那么敏感。这个项目将研究维甲酸控制开关背后的复杂机制，并确定如何操纵它来控制体重。我们的目标是确定大脑在哪里、何时以及如何改变对维甲酸的反应，我们将在对日长变化做出反应的动物(大鼠)中做到这一点。我们还将测试大脑在某些情况下是否比其他情况下产生更多的维甲酸(即夏季与冬季的白天长度)。这个项目的一个重要目标是了解一系列功能步骤，通过这些步骤，白天的长度可以改变大脑中的维甲酸信号，进而我们想要确定维甲酸如何在中枢神经系统水平上改变食物摄取和生长方面的生理状态。鉴于人们认识到维生素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。操纵维甲酸信号通路来影响食物消费和肥胖的可能性可能会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.