Resolving a novel brain circuit controlling appetite and body weight

解决控制食欲和体重的新型大脑回路

• 批准号: MR/P009824/2
• 负责人: Giuseppe D'Agostino
• 金额: $ 71.36万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP009824%2F2
• 关键词: Resolving; novel; brain; circuit; controlling

Here is a startling statistic - more than half the people in the UK are overweight or obese. This is a relatively recent epidemic that is getting worse. Excess body fat primarily results from eating more food than the body requires, calories that are then stored as fat. My research is aimed at understanding what makes us hungry and full and how we can use this information to develop new medications to treat obesity. My second aim is to provide an understanding of obesity that might offer novel strategies for future treatments. According to Dame Sally Davies, Chief Medical Officer for England, obesity is the biggest threat to health and the health of future generations. Obesity increases the risk of developing major illnesses such as type 2 diabetes, cardiovascular disease, cancer and numerous other conditions and it is associated with a reduction in lifespan by approximately 8 years. The objectives of my proposal therefore address a critical health challenge.Dieting should work, but it is not having an impact on the weight and health of the nation; 95% of people who lose weight gain it back. What is needed are multiple approaches to combat this widespread epidemic and my research is focused on the development of new medications. Surprisingly, it is the brain that rules our appetite. Key regions of the brain are responsible for receiving and processing meal information to maintain the equilibrium between hunger and fullness, and to achieve this, specialized nerve cells are wired together in mind boggling networks within our brain. Following a meal, the gut sends chemical messengers into these networks about how much food has been eaten. These messengers activate particular cells in the brain that signal to other brain regions to trigger a decision about whether we have had enough food. The goal of my research is to understand this cross-talk and to decode how hunger and satiety information is passed on between different regions of the brain. I study a brain region called the nucleus of the solitary tract (NTS) because this region acts as a gateway between the gut and the brain, integrating meal-related information and funneling it to the right brain regions so a decision can be made.What happens if more food than the body requires is regularly consumed? Not unlike tolerance to alcohol or a medication, it is possible that the NTS develops a kind of tolerance to nutrient signals and it takes more food for the brain to tell us that we are full. To test this hypothesis, I will turn off specific NTS nerve cells to make them unable to receive and pass on meal-related information and measure food intake and body weight. The aim of these studies is to understand whether such a fault in the system is one of the causes underlying the development of obesity and associated metabolic diseases.It is likely that if we learn more about how the gut and brain communicate, we will be able to send these type of messages to the brain with a medication to reduce appetite and improve obesity. To learn the language of gut-brain communication, we first need to decode the words: the chemicals that these cells use to communicate with each other. My research aims to screen the chemical content of a small group of NTS nerve cells that control appetite to help develop new medications.Another aspect of my research is creating a map of the appetite networks in the brain, like a road atlas. I will use techniques that colour specific brain circuits relying meal-related information. I will also turn these circuits on and off on demand and measure food intake. These studies will allow us to understand which part of the network is crucial for appetite regulation.Overall, I aim to decode the function of a group of nerve cells, clarifying the chemicals they make, and the networks they build within our brains to control appetite - an area of knowledge critical to our understanding and treating the obesity epidemic and improving human health.

这是一个令人震惊的统计数据-超过一半的英国人超重或肥胖。这是一种相对较新的流行病，而且正在恶化。过多的身体脂肪主要是由于吃了比身体需要更多的食物，然后储存为脂肪的卡路里。我的研究旨在了解是什么让我们感到饥饿和饱腹，以及我们如何利用这些信息来开发治疗肥胖的新药。我的第二个目标是提供对肥胖的理解，这可能为未来的治疗提供新的策略。英格兰首席医疗官Dame Sally Davies表示，肥胖是对健康和后代健康的最大威胁。肥胖会增加患重大疾病的风险，如2型糖尿病、心血管疾病、癌症和许多其他疾病，并与寿命缩短约8年有关。因此，我的建议的目标是解决一个关键的健康挑战。节食应该起作用，但它不会对国民的体重和健康产生影响; 95%的减肥者体重会反弹。我们需要的是多种方法来对抗这种广泛的流行病，我的研究重点是新药的开发。令人惊讶的是，正是大脑控制着我们的食欲。大脑的关键区域负责接收和处理膳食信息，以保持饥饿和饱腹之间的平衡，为了实现这一点，专门的神经细胞在我们大脑中令人难以置信的网络中连接在一起。饭后，肠道向这些网络发送化学信使，告诉他们吃了多少食物。这些信使激活大脑中的特定细胞，这些细胞向大脑的其他区域发出信号，以触发我们是否有足够的食物的决定。我的研究目标是了解这种相互作用，并解码饥饿和饱腹感信息如何在大脑的不同区域之间传递。我研究了一个被称为孤束核（NTS）的大脑区域，因为这个区域是肠道和大脑之间的通道，它整合与饮食有关的信息，并将其传送到右脑区域，以便做出决定。如果经常摄入的食物超过身体需要，会发生什么？与对酒精或药物的耐受性不同，NTS可能对营养信号产生了一种耐受性，大脑需要更多的食物才能告诉我们我们吃饱了。为了验证这一假设，我将关闭特定的NTS神经细胞，使它们无法接收和传递与膳食相关的信息，并测量食物摄入量和体重。这些研究的目的是了解这种系统中的故障是否是肥胖和相关代谢疾病发展的潜在原因之一。如果我们更多地了解肠道和大脑如何沟通，我们将能够通过药物将这些类型的信息发送到大脑，以减少食欲并改善肥胖。为了学习肠脑交流的语言，我们首先需要解码这些词：这些细胞用来相互交流的化学物质。我的研究旨在筛选一小群控制食欲的NTS神经细胞的化学成分，以帮助开发新药。我研究的另一个方面是创建大脑食欲网络的地图，就像道路地图集一样。我将使用一些技术，对依赖于饮食相关信息的特定大脑回路进行着色。我也会根据需要打开和关闭这些电路，并测量食物摄入量。这些研究将使我们了解网络的哪一部分对食欲调节至关重要。总的来说，我的目标是解码一组神经细胞的功能，阐明它们产生的化学物质，以及它们在我们大脑中建立的控制食欲的网络--这一知识领域对我们理解和治疗肥胖流行病以及改善人类健康至关重要。

项目成果

Brainstem peptides and peptidergic neurons in the regulation of appetite

• DOI: 10.1016/j.coemr.2022.100339
• 发表时间: 2022-03
• 期刊: Current Opinion in Endocrine and Metabolic Research
• 作者: Giuseppe D’Agostino;S. Luckman

Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects

• DOI: 10.1038/s41385-019-0205-x
• 发表时间: 2019-11-01
• 期刊: MUCOSAL IMMUNOLOGY
• 影响因子: 8
• 作者: Aviello, Gabriella;Singh, Ashish K.;Knaus, Ulla G.
• 通讯作者: Knaus, Ulla G.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

• DOI: 10.1016/j.molmet.2021.101407
• 发表时间: 2022-01
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Costa A;Ai M;Nunn N;Culotta I;Hunter J;Boudjadja MB;Valencia-Torres L;Aviello G;Hodson DJ;Snider BM;Coskun T;Emmerson PJ;Luckman SM;D'Agostino G
• 通讯作者: D'Agostino G

Hypothalamic AgRP neurons exert top-down control on systemic TNF-a release during endotoxemia.

下丘脑 AgRP 神经元在内毒素血症期间对全身 TNF-a 释放进行自上而下的控制。

• DOI: 10.1016/j.cub.2022.09.017
• 发表时间: 2022
• 期刊: CB
• 作者: Boutagouga Boudjadja M