Mapping the neuronal functional architecture underlying appetite control in humans at the extremes of bodyweight

绘制极端体重下人类食欲控制的神经元功能结构

• 批准号: BB/X014207/1
• 负责人: Giles Yeo
• 金额: $ 100.37万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX014207%2F1
• 关键词: Mapping; neuronal; functional; architecture; underlying

Obesity is a growing public health problem. While our changing lifestyle and environment have undoubtedly driven this increase, there is a powerful genetic component that underlies the large variation in human body shape and size in this modern environment. Understanding the mechanisms controlling feeding behaviour that lead to this variability in body-weight will be important in informing any strategy to improve our health in this current food environment. While the preferred model in which to study food intake is clearly in humans, the fact that genetic studies point to a region in the brain called the hypothalamus as having a crucial role in modulating appetite has limited the mechanistic insights achievable through human research. The inaccessibility of the human hypothalamus has, to date, meant our understanding of brain circuits controlling food intake has emerged primarily from mouse studies. However, a recent important collaboration with the MRC Brain Bank Network, has allowed us access to fresh human donor brain samples. These precious samples, coupled with recent developments in single-cell sequencing and in technologies allowing us to visualize single-molecules using fluorescence, have provided us the opportunity to map the functional architecture of the human hypothalamus underlying appetitive behaviour. Over the past three years, we have generated a database of more than 350,000 human hypothalamic cells from eight normal weight donors. This unique resource, even as a work in progress, is already unparalleled in its scope and size. Of interest in of itself, the long-term value of this data, given the role of the hypothalamus in maintaining energy balance, is as a baseline to study this brain region in states of energy imbalance. Building on our growing database, as well as the methodologies and expertise we have accrued, we will map the hypothalamic functional architecture underlying food intake control in the underweight and overweight human brain. Continuing our fruitful collaboration with the MRC Brain Bank Network, we will profile the hypothalami of donors at both extremes of bodyweight. Our goal for a comprehensive human hypothalamic atlas across the weight spectrum will be of utility to basic and translational researchers attempting to better understand the fundamental nature of regulation of energy balance by the hypothalamus. The eventual goal will be to find a way to manipulate these systems to improve the health of the population.

肥胖是日益增长的公共卫生问题。尽管我们不断变化的生活方式和环境无疑驱动了这一增长，但在这种现代环境中，有一个强大的遗传成分是人体形状和大小的巨大变化。了解控制喂养行为的机制，导致体重变异性对于在当前食品环境中改善我们的健康策略的任何策略都很重要。尽管在人类中显然是研究食物摄入量的首选模型，但遗传学研究表明大脑中一个称为下丘脑的区域在调节食欲中起着至关重要的作用，因此限制了通过人类研究获得的机械洞察力。迄今为止，人类下丘脑的无法获得的能力意味着我们对控制食物摄入的脑电路的理解主要来自小鼠研究。但是，最近与MRC脑库网络的重要合作使我们可以访问新鲜的人类供体脑样本。这些珍贵的样品，再加上单细胞测序中的最新发展以及使我们能够使用荧光可视化单分子的技术，为我们提供了映射人类下丘脑供食行为的功能性结构的机会。在过去的三年中，我们从八个正常体重供体中生成了一个超过350,000个人类下丘脑细胞的数据库。即使在进行的工作中，这种独特的资源也已经在其范围和大小上是无与伦比的。鉴于下丘脑在维持能量平衡中的作用，该数据的长期价值是研究该大脑区域在能量不平衡状态下的基准。在我们不断增长的数据库以及我们所累积的方法和专业知识的基础上，我们将绘制体重不足和超重的人脑中食物摄入控制的下丘脑功能结构。继续我们与MRC脑库网络的富有成果的合作，我们将在体重极端介绍捐助者的下丘脑。我们在体重范围内建立全面人类下丘脑地图集的目标将是实用性的，试图更好地理解下丘脑调节能量平衡的基本性质。最终的目标是找到一种操纵这些系统以改善人口健康的方法。