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

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，但在现代环境中，人体形状和大小的巨大变化背后有一个强大的遗传因素。了解控制导致体重变化的摄食行为的机制，对于在当前的食物环境中改善我们的健康的任何策略都很重要。虽然研究食物摄入的首选模型显然是人类，但遗传研究指出大脑中一个称为下丘脑的区域在调节食欲方面起着至关重要的作用，这一事实限制了通过人类研究获得的机制性见解。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脑库网络的重要合作使我们能够获得新鲜的人类捐赠大脑样本。这些珍贵的样本，再加上单细胞测序和技术的最新发展，使我们能够使用荧光可视化单分子，为我们提供了绘制人类下丘脑潜在食欲行为的功能结构的机会。在过去的三年里，我们已经从八个正常体重的捐赠者那里建立了一个超过35万个人类下丘脑细胞的数据库。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能量不平衡状态下大脑区域的基线。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脑库网络的富有成效的合作，我们将在体重的两个极端的捐赠者的下丘脑。我们的目标是一个全面的人类下丘脑地图集的重量谱将实用的基础和翻译研究人员试图更好地了解能量平衡的调节下丘脑的基本性质。最终的目标是找到一种方法来操纵这些系统，以改善人口的健康。

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.