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种增长，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。了解控制进食行为的机制，从而导致体重的这种变化，对于在当前的食物环境中提供任何改善我们健康的策略都是重要的。虽然研究食物摄入的首选模型显然是在人类身上，但基因研究指出，大脑中一个名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见解。到目前为止，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于对老鼠的研究。然而，最近与MRC脑库网络的一次重要合作，使我们能够获得新鲜的人类供体大脑样本。这些珍贵的样本，再加上单细胞测序的最新发展，以及利用荧光可视化单分子的技术，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，我们建立了一个数据库包含了来自8个正常体重捐献者的超过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，这些数据本身的长期价值是作为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，我们将绘制出在体重过轻和超重的人类大脑中控制食物摄入的下丘脑功能结构。继续我们与MRC脑库网络卓有成效的合作，我们将对两个极端体重的捐赠者的下丘脑进行分析。我们的目标是在体重谱上建立一个全面的人类下丘脑图谱，这将有助于基础和转化研究人员更好地理解下丘脑调节能量平衡的基本性质。最终的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。

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.