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

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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.