Map of human brain’s appetite centre could enable new treatments for obesity and diabetes

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"... While much of our knowledge of the hypothalamus comes from animal studies, especially in mice, translating these findings to humans has long been a challenge. HYPOMAP bridges this gap by providing an atlas of the individual cells within the human hypothalamus. This resource not only charts over 450 unique cell types but also highlights key differences between the human and mouse hypothalamus — differences that have major implications for drug development. ...

“HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity. ...

researchers ... used cutting-edge technologies to analyse over 400,000 cells from 18 human donors. HYPOMAP allows researchers to pinpoint specific cell types, understand their genetic profiles, and explore how they interact with neighbouring cells. This detailed cellular resolution offers invaluable insights into the circuits that regulate appetite and energy balance, as well as other functions such as sleep and stress responses. ..."

From the abstract:

"The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and neuro circuitries have, until recently, emerged primarily from rodent studies.

Here we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the ‘HYPOMAP’. Although conservation of neuronal cell types between humans and mice, as based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments.

Out of the 452 hypothalamic cell types, we find that 291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 ‘effector’ genes.

Rare deleterious variants in six of these (MC4R, PCSK1, POMC, CALCR, BSN and CORO1A) associate with BMI at population level, and CORO1A has not been linked previously to BMI.

Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify new druggable targets for treating a wide range of conditions, including reproductive, circadian and metabolic disorders."

Map of brain’s appetite centre could enable new treatments for obesity and diabetes | University of Cambridge "Scientists have created the most detailed map to date of the human hypothalamus, a crucial brain region that regulates body weight, appetite, sleep, and stress."

A comprehensive spatio-cellular map of the human hypothalamus (open access)

Fig. 1: Integrated snRNA-seq reference atlas of the human hypothalamus.

Fig. 2: Cell-type taxonomy of the human hypothalamus.