A comprehensive spatio-cellular map of the human hypothalamus
The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions<sup>1</sup>. However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies<sup>2,3</sup>. 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.
Authors
- Henning Hvid (ORCID: https://orcid.org/0000-0002-3667-4141)
- Sofia Lundh (ORCID: https://orcid.org/0000-0002-4552-0312)
- Paul Klemm (ORCID: https://orcid.org/0000-0002-5985-1737)
- Brian Y.H. Lam (ORCID: https://orcid.org/0000-0002-3638-9025)
- John R. B. Perry (ORCID: https://orcid.org/0000-0001-6483-3771)
- Kara Rainbow (ORCID: https://orcid.org/0000-0002-8089-0693)
- Georgina K.C. Dowsett (ORCID: https://orcid.org/0000-0002-2134-8554)
- Marta Porniece (ORCID: https://orcid.org/0000-0003-2330-5846)
- Katherine A. Kentistou (ORCID: https://orcid.org/0000-0002-5816-664X)
- Joseph Polex-Wolf (ORCID: https://orcid.org/0000-0002-0441-8872)
- Giles S.H. Yeo (ORCID: https://orcid.org/0000-0001-8823-3615)
- Lukas Steuernagel (ORCID: https://orcid.org/0000-0003-0043-1436)
- Katarzyna Kania (ORCID: https://orcid.org/0000-0002-0673-596X)
- Charles Pyke (ORCID: https://orcid.org/0000-0002-7286-5009)
- John A. Tadross (ORCID: https://orcid.org/0000-0002-8424-1252)
- Lotte Bjerre Knudsen (ORCID: https://orcid.org/0000-0002-2439-7116)
- Jens C. Brüning (ORCID: https://orcid.org/0000-0002-6619-0092)
Institutions
- University of Cologne (DE)
- Novo Nordisk (Denmark) (DK)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Cancer Research UK Cambridge Center (GB)
- Max Planck Institute for Metabolism Research (DE)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Genomics (United Kingdom) (GB)
- University Hospital Cologne (DE)
- MRC Epidemiology Unit (GB)
- German Center for Diabetes Research (DE)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1038/s41586-024-08504-8
- Citations
- 65
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 57.62
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council