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The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour

下丘脑星形胶质细胞在摄食行为稳态调节中的作用

基本信息

批准号：
MR/N012763/1
负责人：
Kate Ellacott
金额：
$ 56.44万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN012763%2F1
关键词：
role hypothalamic astrocytes homeostatic regulation

项目摘要

Disturbed regulation of food intake contributes to obesity, which is a major, and growing, public health issue in the U.K. Obesity already affects greater than 25% of the adult population and is costing the NHS an estimated £4.2billion annually. To enable scientists and pharmaceutical companies to develop the most effective therapeutic interventions for diseases like obesity, where the body's mechanisms regulating food intake are not working correctly, it is critical that we develop a thorough and detailed understanding of how food intake is regulated normally.Mechanisms based within the central nervous system (CNS) contribute pivotally to control of food intake and body weight. Although many brain areas play a role in control of feeding behaviours, a region known as the hypothalamus is vital for orchestrating the regulation of food intake, something that occurs through both nervous and hormonal signalling processes. Basic research, like that proposed here, has already identified critical circuits of nerve cells within the hypothalamus that are vital for the regulation of food intake. These include specific neurons which increase the motivation to eat when they are active and different neurons which can produce the opposite outcome, namely suppressing food intake. Although neurons are the best known cell type within the brain, they are not the most abundant. This distinction falls to non-neuronal cells known as glia. The functional involvement of glia in the regulation of food intake remains poorly understood, although these cells can unquestionably influence other bodily functions. For example, we know an important class of glial cells known as astroglia can directly regulate the activity of hypothalamic nerve circuits that control reproduction and blood pressure, demonstrating precedence for a critical contribution of astroglia to the regulation of key body processes. Recently, we discovered that genetically altering astroglial signalling in mice, increased food intake when the animals were given a palatable high-fat diet, supporting for the first time, a role these cells in a process that acutely regulates feeding. The overall purpose of this project is to follow up on this important finding, and to identify the mechanisms by which astroglia regulate food intake in response to a high-fat diet i.e. nutrient excess, and also to establish if similar mechanisms are involved in the feeding response to the opposite extreme, nutritional insufficiency e.g. fasting.Our specific aims are:1. To identify states of nutritional imbalance that cause astroglial activation in the hypothalamus.2. To establish the role of astroglia in modulating the electrical activity of hypothalamic neurons that regulate feeding.3. To determine how altering signalling in hypothalamic astroglia impacts food intake in response to in vivo nutritional imbalance.4. To understand how manipulating astroglial signalling alters overall metabolism.An improved understanding of the mechanisms by which food intake is regulated will benefit other scientists and clinicians working towards developing new therapies for disorders of food intake including obesity and anorexia.

食物摄入失调会导致肥胖，这是英国一个主要的、日益严重的公共健康问题。肥胖已经影响了超过25%的成年人口，每年给英国国家医疗服务体系（NHS）造成约42亿英镑的损失。为了使科学家和制药公司能够开发最有效的治疗干预措施，如肥胖等疾病，人体调节食物摄入的机制不能正常工作，我们必须对食物摄入如何正常调节有一个全面而详细的了解。基于中枢神经系统（CNS）的机制对控制食物摄入和体重起关键作用。虽然大脑的许多区域都在控制进食行为中发挥作用，但下丘脑区域对于协调食物摄入的调节至关重要，这是通过神经和激素信号过程发生的。基础研究，就像这里提出的那样，已经确定了下丘脑内神经细胞的关键回路，这些回路对调节食物摄入至关重要。其中包括一些特定的神经元，当它们活跃时，它们会增加进食的动机，而另一些神经元则会产生相反的结果，即抑制食物摄入。虽然神经元是大脑中最著名的细胞类型，但它们并不是最丰富的。这种区别属于被称为神经胶质的非神经元细胞。神经胶质细胞在调节食物摄入方面的功能参与仍然知之甚少，尽管这些细胞毫无疑问可以影响其他身体功能。例如，我们知道一类被称为星形胶质细胞的重要胶质细胞可以直接调节控制生殖和血压的下丘脑神经回路的活动，这证明了星形胶质细胞对调节关键身体过程的重要贡献。最近，我们发现改变老鼠体内星形胶质细胞信号的基因，当动物被给予美味的高脂肪食物时，它们的食物摄入量增加，首次支持了这些细胞在严格调节进食过程中的作用。该项目的总体目的是跟进这一重要发现，并确定星形胶质细胞在高脂肪饮食（即营养过剩）下调节食物摄入的机制，并确定是否类似的机制参与了相反极端的喂养反应，如营养不足，如禁食。我们的具体目标是：1。确定导致下丘脑星形胶质细胞激活的营养不平衡状态。确立星形胶质细胞在调节调节进食的下丘脑神经元电活动中的作用。为了确定下丘脑星形胶质细胞信号的改变如何影响体内营养不平衡时的食物摄入。了解操纵星形胶质信号如何改变整体代谢。对食物摄入调节机制的进一步了解将有利于其他科学家和临床医生致力于开发治疗食物摄入失调（包括肥胖和厌食症）的新疗法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.

星形胶质细胞对炎症的代谢反应受到核因子 kappa B 信号传导的调节。

DOI：
10.1002/glia.23835
发表时间：
2020
期刊：
Glia
影响因子：
6.2
作者：
Robb JL
通讯作者：
Robb JL

Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes.

DOI：
10.1007/s00125-018-4744-6
发表时间：
2019-01
期刊：
Diabetologia
影响因子：
8.2
作者：
Weightman Potter PG;Vlachaki Walker JM;Robb JL;Chilton JK;Williamson R;Randall AD;Ellacott KLJ;Beall C
通讯作者：
Beall C

Changes in neuronal activity across the mouse ventromedial nucleus of the hypothalamus in response to low glucose: Evaluation using an extracellular multi-electrode array approach.

小鼠下丘脑腹内侧核神经元活动的变化响应低葡萄糖：使用细胞外多电极阵列方法进行评估。