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.

肥胖是一个日益严重的公共卫生问题。虽然我们不断变化的生活方式和环境无疑推动了这种增长，但在现代环境下，人体形状和尺寸的巨大变化背后有一个强大的遗传因素。了解导致体重变化的进食行为控制机制对于制定在当前食品环境下改善健康的策略非常重要。虽然研究食物摄入的首选模型显然是在人类身上，但基因研究表明大脑中一个称为下丘脑的区域在调节食欲方面发挥着至关重要的作用，这一事实限制了通过人类研究可实现的机制见解。迄今为止，人类下丘脑的不可接近性意味着我们对控制食物摄入的大脑回路的理解主要来自小鼠研究。然而，最近与 MRC 脑库网络的一项重要合作使我们能够获得新鲜的人类捐赠者大脑样本。这些珍贵的样本，加上单细胞测序和使我们能够利用荧光可视化单分子的技术的最新发展，为我们提供了绘制人类下丘脑食欲行为背后的功能结构的机会。在过去的三年里，我们生成了一个数据库，其中包含来自八名正常体重捐赠者的超过 350,000 个人类下丘脑细胞。这一独特的资源，即使是一项正在进行的工作，其范围和规模也已经是无与伦比的。考虑到下丘脑在维持能量平衡中的作用，这些数据的长期价值本身就很有趣，可以作为研究处于能量不平衡状态的该大脑区域的基线。基于我们不断增长的数据库以及我们积累的方法和专业知识，我们将绘制体重不足和超重人类大脑中食物摄入控制基础的下丘脑功能结构。继续与 MRC 脑库网络富有成效的合作，我们将描绘体重两个极端的捐赠者的下丘脑。我们的目标是建立一个涵盖体重范围的全面的人类下丘脑图谱，这对于试图更好地理解下丘脑能量平衡调节的基本性质的基础和转化研究人员来说将是有用的。最终目标将是找到一种方法来操纵这些系统以改善人口的健康。