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健康问题。虽然我们不断变化的生活方式和环境无疑推动了这一增长，但在这个现代环境中，人体形状和体型的巨大差异背后有一个强大的基因成分。了解导致体重变化的摄食行为控制机制，对于在目前的食物环境中改善我们的健康战略具有重要意义。虽然研究食物摄入量的首选模型显然是在人类身上，但遗传研究指出，大脑中一个名为下丘脑的区域在调节食欲方面发挥着关键作用，这一事实限制了通过人类研究实现的机械性洞察。到目前为止，人类下丘脑的不可访问性意味着我们对控制食物摄入量的大脑回路的了解主要是从小鼠的研究中产生的。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，再加上单细胞测序和允许我们使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潜在食欲行为的功能结构图的机会。在过去的三年里，我们已经建立了一个数据库，其中包括来自8名正常体重捐赠者的超过35万个人类下丘脑细胞。这一独特的资源，即使作为一项正在进行的工作，其范围和规模也已经是无与伦比的。有趣的是，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是研究这一大脑区域处于能量失衡状态的基线。在我们不断增长的数据库以及我们积累的方法和专业知识的基础上，我们将绘制出在体重不足和超重的人脑中进行食物摄取控制的下丘脑功能结构图。继续我们与MRC脑库网络富有成效的合作，我们将描绘体重两极的捐赠者的下丘脑。我们的目标是建立一个全面的人类下丘脑体重图谱，这将对试图更好地理解下丘脑调节能量平衡的基本性质的基础和翻译研究人员有用。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。