Amino acid sensing by hypothalamic tanycytes

近三分之二的英国人口超重或肥胖。这种超重会增加过早死亡和一系列疾病的风险，如糖尿病和中风，从而极大地降低生活质量。位于大脑底部的下丘脑通过调节食物摄入量(通过饥饿感和饱腹感)以及脂肪的沉积和能量的消耗(如热量产生和活动)来控制体重。了解大脑如何发出饥饿和饱腹感的信号是我们开始制定策略减少人群超重发生率的一种方式。食物中的氨基酸含量是饱腹感的强大决定因素。当血浆中的氨基酸水平较高时，饱腹感也会随之升高。氨基酸在大脑中被检测到。到目前为止，已经描述了四个不同的脑区，神经细胞对氨基酸浓度的变化做出反应。我们建议研究第五种机制，它是独特的，因为它不是由神经细胞介导的，而是由下丘脑中被称为张力细胞的特殊胶质细胞介导的。我们已经证明，张力细胞对氨基酸做出反应，这可能是通过激活一种感受器，该感受器也发生在舌头的味蕾中，该感受器调节到“鲜味”--L的味道--氨基酸。这个项目的总体目的是了解为什么可变细胞感知大脑中的氨基酸，以及这些信息的用途。我们的具体目标是：1.表征可变细胞检测和发送氨基酸浓度的机制；2.确定通过伸缩细胞感知氨基酸是否与这些细胞中其他形式的营养感知相互作用--特别是它们感知葡萄糖的能力；3.测试通过伸缩细胞感知氨基酸的特性是否可以通过饮食(禁食，食物中氨基酸的数量)来改变；4.研究通过张力细胞的氨基酸感应在决定食物偏好、食物摄入量和最终控制体重方面的贡献。了解这种新的氨基酸感应途径的机制和功能作用对临床医生和相关的卫生专业人员、商业组织、相关的医疗慈善机构、政府机构和公众都有许多好处。商业公司可能会利用我们的工作来开发减少食欲的新型食品添加剂，或者重新配制食物以提高饱腹感。根据我们的工作，临床医生、营养师和相关的医疗慈善机构可能能够修改对不同类别患者的饮食和饮食模式的建议，以促进健康饮食和减肥。政府机构也许能够修改其关于食品行业的政策，并向公众提供建议，以促进健康饮食。

Nearly two thirds of the UK population is overweight or obese. This excess weight elevates the risk of premature death and a range of illnesses, such as diabetes and stroke, which greatly reduce quality of life. The hypothalamus at the base of the brain controls body weight by regulating food intake (though feelings of hunger and satiety), and also deposition of fat and expenditure of energy (as heat production and activity). Understanding how the brain signals hunger and satiety is one way in which we can start to develop strategies to reduce the incidence of excess weight in the population.The amino acid content of food is a powerful determinant of satiety. When plasma levels of amino acids are high, then so is the feeling of satiety. Amino acids are detected in the brain. So far four different brain regions have been described in which nerve cells respond to variations in the concentrations of amino acids. We propose to examine a 5th mechanism, which is unique as it is not mediated by nerve cells, but rather by specialized glial cells in the hypothalamus called tanycytes. We have already shown that tanycytes respond to amino acids, and that this may be via the activation of a receptor that also occurs in the taste buds of the tongue which is tuned to the "umami flavour" -the taste of L-amino acids. The overall purpose of this project is to understand why tanycytes sense amino acids in the brain and what this information is used for.Our specific aims are to: 1. Characterize the mechanisms by which tanycytes detect and signal amino acid concentration; 2. Determine whether amino acid sensing via tanycytes interacts with other modalities of nutrient sensing in these cells -specifically their ability to sense glucose; 3. Test whether the properties of amino acid sensing via tanycytes can be altered by diet (fasting, amount of amino acids in food); 4. Examine the contribution of amino acid sensing via tanycytes to determination of food preferences, the amount of food intake, and ultimately control of body weight.Understanding the mechanisms and functional roles of this new amino acid sensing pathway has many benefits for clinicians and related health professionals; commercial organizations; relevant medical charities; government agencies; and the public. Commercial companies may use our work to develop new types of food additive that reduce appetite, or to reformulate food so that it promotes feelings of satiety. In the light of our work, clinicians, dieticians, and relevant medical charities, may be able to modify advice on diet and eating patterns to various classes of patient to promote healthy eating and weight loss. Government agencies may be able to revise their policies with respect to the food industry and advice to the public to promote healthy eating.