{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:32:08Z","timestamp":1792647128582,"version":"4.5.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"8055","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2025,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions\n                    <jats:sup>1<\/jats:sup>\n                    . However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies\n                    <jats:sup>2,3<\/jats:sup>\n                    . 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 \u2018HYPOMAP\u2019. Although conservation of neuronal cell types between humans and mice, as\u00a0based 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\u00a0291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 \u2018effector\u2019 genes. Rare deleterious variants in six of these (\n                    <jats:italic>MC4R<\/jats:italic>\n                    ,\n                    <jats:italic>PCSK1<\/jats:italic>\n                    ,\n                    <jats:italic>POMC<\/jats:italic>\n                    ,\n                    <jats:italic>CALCR<\/jats:italic>\n                    ,\n                    <jats:italic>BSN<\/jats:italic>\n                    and\n                    <jats:italic>CORO1A<\/jats:italic>\n                    ) associate with BMI at population level, and\n                    <jats:italic>CORO1A<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08504-8","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T11:05:58Z","timestamp":1738753558000},"page":"708-716","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["A comprehensive spatio-cellular map of the human hypothalamus"],"prefix":"10.1038","volume":"639","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8424-1252","authenticated-orcid":false,"given":"John A.","family":"Tadross","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0043-1436","authenticated-orcid":false,"given":"Lukas","family":"Steuernagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina K. C.","family":"Dowsett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-664X","authenticated-orcid":false,"given":"Katherine A.","family":"Kentistou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4552-0312","authenticated-orcid":false,"given":"Sofia","family":"Lundh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2330-5846","authenticated-orcid":false,"given":"Marta","family":"Porniece","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-1737","authenticated-orcid":false,"given":"Paul","family":"Klemm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Rainbow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Hvid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0441-8872","authenticated-orcid":false,"given":"Joseph","family":"Polex-Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2439-7116","authenticated-orcid":false,"given":"Lotte Bjerre","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Pyke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-3771","authenticated-orcid":false,"given":"John R. B.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-9025","authenticated-orcid":false,"given":"Brian Y. H.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6619-0092","authenticated-orcid":false,"given":"Jens C.","family":"Br\u00fcning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8823-3615","authenticated-orcid":false,"given":"Giles S. H.","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"8504_CR1","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1126\/science.adh8488","volume":"382","author":"H Fong","year":"2023","unstructured":"Fong, H., Zheng, J. & Kurrasch, D. The structural and functional complexity of the integrative hypothalamus. Science 382, 388\u2013394 (2023).","journal-title":"Science"},{"key":"8504_CR2","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41576-021-00414-z","volume":"23","author":"RJF Loos","year":"2022","unstructured":"Loos, R. J. F. & Yeo, G. S. H. The genetics of obesity: from discovery to biology. Nat. Rev. Genet. 23, 120\u2013133 (2022).","journal-title":"Nat. Rev. Genet."},{"key":"8504_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101206","volume":"48","author":"GSH Yeo","year":"2021","unstructured":"Yeo, G. S. H. et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy. Mol. Metab. 48, 101206 (2021).","journal-title":"Mol. Metab."},{"key":"8504_CR4","doi-asserted-by":"publisher","DOI":"10.1111\/jne.13080","volume":"34","author":"SB Seminara","year":"2022","unstructured":"Seminara, S. B. & Topaloglu, A. K. Review of human genetic and clinical studies directly relevant to GnRH signalling. J. Neuroendocrinol. 34, e13080 (2022).","journal-title":"J. Neuroendocrinol."},{"key":"8504_CR5","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/s41586-021-04088-9","volume":"599","author":"BYH Lam","year":"2021","unstructured":"Lam, B. Y. H. et al. MC3R links nutritional state to childhood growth and the timing of puberty. Nature 599, 436\u2013441 (2021).","journal-title":"Nature"},{"key":"8504_CR6","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1056\/NEJMoa2032183","volume":"384","author":"JPH Wilding","year":"2021","unstructured":"Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989\u20131002 (2021).","journal-title":"N. Engl. J. Med."},{"key":"8504_CR7","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1056\/NEJMoa2206038","volume":"387","author":"AM Jastreboff","year":"2022","unstructured":"Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205\u2013216 (2022).","journal-title":"N. Engl. J. Med."},{"key":"8504_CR8","doi-asserted-by":"publisher","first-page":"4473","DOI":"10.1172\/JCI75276","volume":"124","author":"A Secher","year":"2014","unstructured":"Secher, A. et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124, 4473\u20134488 (2014).","journal-title":"J. Clin. Invest."},{"key":"8504_CR9","doi-asserted-by":"publisher","first-page":"e133429","DOI":"10.1172\/jci.insight.133429","volume":"5","author":"S Gabery","year":"2020","unstructured":"Gabery, S. et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5, e133429 (2020).","journal-title":"JCI Insight"},{"key":"8504_CR10","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s42255-021-00363-1","volume":"3","author":"MQ Ludwig","year":"2021","unstructured":"Ludwig, M. Q. et al. A genetic map of the mouse dorsal vagal complex and its role in obesity. Nat. Metab. 3, 530\u2013545 (2021).","journal-title":"Nat. Metab."},{"key":"8504_CR11","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1097\/MED.0000000000000798","volume":"30","author":"CM Trapp","year":"2023","unstructured":"Trapp, C. M. & Censani, M. Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity. Curr. Opin. Endocrinol. Diabetes Obes. 30, 136\u2013140 (2023).","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"8504_CR12","doi-asserted-by":"publisher","DOI":"10.1126\/science.add7046","volume":"382","author":"K Siletti","year":"2023","unstructured":"Siletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. Science 382, eadd7046 (2023).","journal-title":"Science"},{"key":"8504_CR13","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1038\/s41592-018-0229-2","volume":"15","author":"R Lopez","year":"2018","unstructured":"Lopez, R., Regier, J., Cole, M. B., Jordan, M. I. & Yosef, N. Deep generative modeling for single-cell transcriptomics. Nat. Methods 15, 1053\u20131058 (2018).","journal-title":"Nat. Methods"},{"key":"8504_CR14","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1038\/s42255-022-00657-y","volume":"4","author":"L Steuernagel","year":"2022","unstructured":"Steuernagel, L. et al. HypoMap-a unified single-cell gene expression atlas of the murine hypothalamus. Nat. Metab. 4, 1402\u20131419 (2022).","journal-title":"Nat. Metab."},{"key":"8504_CR15","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf6251","volume":"9","author":"BR Herb","year":"2023","unstructured":"Herb, B. R. et al. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus. Sci. Adv. 9, eadf6251 (2023).","journal-title":"Sci. Adv."},{"key":"8504_CR16","doi-asserted-by":"publisher","first-page":"R161","DOI":"10.1530\/JOE-16-0256","volume":"232","author":"RA Romanov","year":"2017","unstructured":"Romanov, R. A., Alpar, A., Hokfelt, T. & Harkany, T. Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus. J. Endocrinol. 232, R161\u2013R172 (2017).","journal-title":"J. Endocrinol."},{"key":"8504_CR17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2303077120","volume":"120","author":"IA Hatton","year":"2023","unstructured":"Hatton, I. A. et al. The human cell count and size distribution. Proc. Natl Acad. Sci. USA 120, e2303077120 (2023).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"8504_CR18","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/s41587-021-01139-4","volume":"40","author":"V Kleshchevnikov","year":"2022","unstructured":"Kleshchevnikov, V. et al. Cell2location maps fine-grained cell types in spatial transcriptomics. Nat. Biotechnol. 40, 661\u2013671 (2022).","journal-title":"Nat. Biotechnol."},{"key":"8504_CR19","doi-asserted-by":"publisher","first-page":"bqab141","DOI":"10.1210\/endocr\/bqab141","volume":"162","author":"T Khodai","year":"2021","unstructured":"Khodai, T. & Luckman, S. M. Ventromedial nucleus of the hypothalamus neurons under the magnifying glass. Endocrinology 162, bqab141 (2021).","journal-title":"Endocrinology"},{"key":"8504_CR20","doi-asserted-by":"publisher","DOI":"10.1126\/science.adc9020","volume":"378","author":"F Endo","year":"2022","unstructured":"Endo, F. et al. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science 378, eadc9020 (2022).","journal-title":"Science"},{"key":"8504_CR21","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nn.4495","volume":"20","author":"JN Campbell","year":"2017","unstructured":"Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484\u2013496 (2017).","journal-title":"Nat. Neurosci."},{"key":"8504_CR22","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1177\/0091270011419854","volume":"52","author":"ML Reitman","year":"2012","unstructured":"Reitman, M. L. et al. Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients. J. Clin. Pharmacol. 52, 1306\u20131316 (2012).","journal-title":"J. Clin. Pharmacol."},{"key":"8504_CR23","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41593-021-00854-0","volume":"24","author":"N Biglari","year":"2021","unstructured":"Biglari, N. et al. Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat. Neurosci. 24, 913\u2013929 (2021).","journal-title":"Nat. Neurosci."},{"key":"8504_CR24","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-023-05906-7","author":"DJ Drucker","year":"2023","unstructured":"Drucker, D. J. & Holst, J. J. The expanding incretin universe: from basic biology to clinical translation. Diabetologia https:\/\/doi.org\/10.1007\/s00125-023-05906-7 (2023).","journal-title":"Diabetologia"},{"key":"8504_CR25","doi-asserted-by":"publisher","first-page":"e157515","DOI":"10.1172\/JCI157515","volume":"133","author":"AC Rupp","year":"2023","unstructured":"Rupp, A. C. et al. Suppression of food intake by Glp1r\/Lepr-coexpressing neurons prevents obesity in mouse models. J. Clin. Invest. 133, e157515 (2023).","journal-title":"J. Clin. Invest."},{"key":"8504_CR26","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1126\/science.adj2537","volume":"385","author":"KS Kim","year":"2024","unstructured":"Kim, K. S. et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science 385, 438\u2013446 (2024).","journal-title":"Science"},{"key":"8504_CR27","doi-asserted-by":"publisher","first-page":"3641","DOI":"10.1093\/hmg\/ddy271","volume":"27","author":"L Yengo","year":"2018","unstructured":"Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum. Mol. Genet. 27, 3641\u20133649 (2018).","journal-title":"Hum. Mol. Genet."},{"key":"8504_CR28","doi-asserted-by":"publisher","first-page":"e55851","DOI":"10.7554\/eLife.55851","volume":"9","author":"PN Timshel","year":"2020","unstructured":"Timshel, P. N., Thompson, J. J. & Pers, T. H. Genetic mapping of etiologic brain cell types for obesity. eLife 9, e55851 (2020).","journal-title":"eLife"},{"key":"8504_CR29","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12843","volume":"22","author":"L Zhang","year":"2023","unstructured":"Zhang, L. et al. A genome-wide association study identified new variants associated with mathematical abilities in Chinese children. Genes Brain Behav. 22, e12843 (2023).","journal-title":"Genes Brain Behav."},{"key":"8504_CR30","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1126\/science.aar4983","volume":"361","author":"SX Luo","year":"2018","unstructured":"Luo, S. X. et al. Regulation of feeding by somatostatin neurons in the tuberal nucleus. Science 361, 76\u201381 (2018).","journal-title":"Science"},{"key":"8504_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100168","volume":"2","author":"KJ Karczewski","year":"2022","unstructured":"Karczewski, K. J. et al. Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes. Cell Genom. 2, 100168 (2022).","journal-title":"Cell Genom."},{"key":"8504_CR32","doi-asserted-by":"publisher","first-page":"eabf8683","DOI":"10.1126\/science.abf8683","volume":"373","author":"P Akbari","year":"2021","unstructured":"Akbari, P. et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science 373, eabf8683 (2021).","journal-title":"Science"},{"key":"8504_CR33","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/S0092-8674(00)81865-6","volume":"88","author":"D Huszar","year":"1997","unstructured":"Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131\u2013141 (1997).","journal-title":"Cell"},{"key":"8504_CR34","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/2407","volume":"20","author":"C Vaisse","year":"1998","unstructured":"Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113\u2013114 (1998).","journal-title":"Nat. Genet."},{"key":"8504_CR35","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/2404","volume":"20","author":"GS Yeo","year":"1998","unstructured":"Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111\u2013112 (1998).","journal-title":"Nat. Genet."},{"key":"8504_CR36","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/ng0797-303","volume":"16","author":"RS Jackson","year":"1997","unstructured":"Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303\u2013306 (1997).","journal-title":"Nat. Genet."},{"key":"8504_CR37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/509","volume":"19","author":"H Krude","year":"1998","unstructured":"Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155\u2013157 (1998).","journal-title":"Nat. Genet."},{"key":"8504_CR38","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/S0092-8674(00)81736-5","volume":"94","author":"S Butz","year":"1998","unstructured":"Butz, S., Okamoto, M. & Sudhof, T. C. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94, 773\u2013782 (1998).","journal-title":"Cell"},{"key":"8504_CR39","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/s41588-024-01694-x","volume":"56","author":"Y Zhao","year":"2024","unstructured":"Zhao, Y. et al. Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease. Nat. Genet. 56, 579\u2013584 (2024).","journal-title":"Nat. Genet."},{"key":"8504_CR40","doi-asserted-by":"publisher","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","volume":"44","author":"NA O\u2019Leary","year":"2016","unstructured":"O\u2019Leary, N. A. et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44, D733\u2013D745 (2016).","journal-title":"Nucleic Acids Res."},{"key":"8504_CR41","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/s41593-020-00794-1","volume":"24","author":"UC Eze","year":"2021","unstructured":"Eze, U. C., Bhaduri, A., Haeussler, M., Nowakowski, T. J. & Kriegstein, A. R. Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia. Nat. Neurosci. 24, 584\u2013594 (2021).","journal-title":"Nat. Neurosci."},{"key":"8504_CR42","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41591-021-01349-y","volume":"27","author":"KH Wade","year":"2021","unstructured":"Wade, K. H. et al. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. Nat. Med. 27, 1088\u20131096 (2021).","journal-title":"Nat. Med."},{"key":"8504_CR43","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/S0140-6736(23)01163-7","volume":"402","author":"JP Frias","year":"2023","unstructured":"Frias, J. P. et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 402, 720\u2013730 (2023).","journal-title":"Lancet"},{"key":"8504_CR44","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/j.cmet.2019.07.013","volume":"30","author":"AE Adriaenssens","year":"2019","unstructured":"Adriaenssens, A. E. et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30, 987\u2013996 e986 (2019).","journal-title":"Cell Metab."},{"key":"8504_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101240","volume":"53","author":"GKC Dowsett","year":"2021","unstructured":"Dowsett, G. K. C. et al. A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing. Mol. Metab. 53, 101240 (2021).","journal-title":"Mol. Metab."},{"key":"8504_CR46","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41588-017-0011-x","volume":"50","author":"V Turcot","year":"2018","unstructured":"Turcot, V. et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat. Genet. 50, 26\u201341 (2018).","journal-title":"Nat. Genet."},{"key":"8504_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101139","volume":"46","author":"JE Campbell","year":"2021","unstructured":"Campbell, J. E. Targeting the GIPR for obesity: to agonize or antagonize? Potential mechanisms. Mol. Metab. 46, 101139 (2021).","journal-title":"Mol. Metab."},{"key":"8504_CR48","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s42255-023-00966-w","volume":"6","author":"MM Veniant","year":"2024","unstructured":"Veniant, M. M. et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat. Metab. 6, 290\u2013303 (2024).","journal-title":"Nat. Metab."},{"key":"8504_CR49","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/B978-0-12-820107-7.00016-1","volume":"180","author":"V Prevot","year":"2021","unstructured":"Prevot, V., Nogueiras, R. & Schwaninger, M. Tanycytes in the infundibular nucleus and median eminence and their role in the blood-brain barrier. Handb. Clin. Neurol. 180, 253\u2013273 (2021).","journal-title":"Handb. Clin. Neurol."},{"key":"8504_CR50","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1016\/j.cell.2024.05.055","volume":"187","author":"M Schott","year":"2024","unstructured":"Schott, M. et al. Open-ST: high-resolution spatial transcriptomics in 3D. Cell 187, 3953\u20133972 e3926 (2024).","journal-title":"Cell"},{"key":"8504_CR51","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1038\/s41592-023-01943-7","volume":"20","author":"SJ Fleming","year":"2023","unstructured":"Fleming, S. J. et al. Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender. Nat. Methods 20, 1323\u20131335 (2023).","journal-title":"Nat. Methods"},{"key":"8504_CR52","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0947-7","volume":"17","author":"AT Lun","year":"2016","unstructured":"Lun, A. T., Bach, K. & Marioni, J. C. Pooling across cells to normalize single-cell RNA sequencing data with many zero counts. Genome Biol. 17, 75 (2016).","journal-title":"Genome Biol."},{"key":"8504_CR53","doi-asserted-by":"publisher","first-page":"979","DOI":"10.12688\/f1000research.73600.1","volume":"10","author":"PL Germain","year":"2021","unstructured":"Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res 10, 979 (2021).","journal-title":"F1000Res"},{"key":"8504_CR54","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573\u20133587 e3529 (2021).","journal-title":"Cell"},{"key":"8504_CR55","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41587-021-01206-w","volume":"40","author":"A Gayoso","year":"2022","unstructured":"Gayoso, A. et al. A Python library for probabilistic analysis of single-cell omics data. Nat. Biotechnol. 40, 163\u2013166 (2022).","journal-title":"Nat. Biotechnol."},{"key":"8504_CR56","doi-asserted-by":"crossref","unstructured":"Zhang Fern, X. & Brodley, C. E. Solving cluster ensemble problems by bipartite graph partitioning. ICML \u201804: Proceedings of the Twenty-first International Conference on Machine Learning (eds Greiner, R. & Schuurmans, D.) 36 (ACM, 2004).","DOI":"10.1145\/1015330.1015414"},{"key":"8504_CR57","doi-asserted-by":"publisher","first-page":"e91","DOI":"10.1093\/nar\/gkab481","volume":"49","author":"M Peng","year":"2021","unstructured":"Peng, M. et al. Cell type hierarchy reconstruction via reconciliation of multi-resolution cluster tree. Nucleic Acids Res. 49, e91 (2021).","journal-title":"Nucleic Acids Res."},{"key":"8504_CR58","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1109\/TCBB.2021.3094650","volume":"18","author":"S Liang","year":"2021","unstructured":"Liang, S., Liang, Q., Chen, R. & Chen, K. Stratified test accurately identifies differentially expressed genes under batch effects in single-cell data. IEEE\/ACM Trans. Comput. Biol. Bioinform. 18, 2072\u20132079 (2021).","journal-title":"IEEE\/ACM Trans. Comput. Biol. Bioinform."},{"key":"8504_CR59","doi-asserted-by":"crossref","first-page":"D682","DOI":"10.1093\/nar\/gkz1138","volume":"48","author":"AD Yates","year":"2020","unstructured":"Yates, A. D. et al. Ensembl 2020. Nucleic Acids Res. 48, D682\u2013D688 (2020).","journal-title":"Nucleic Acids Res."},{"key":"8504_CR60","doi-asserted-by":"publisher","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","volume":"49","author":"C UniProt","year":"2021","unstructured":"UniProt, C. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 49, D480\u2013D489 (2021).","journal-title":"Nucleic Acids Res."},{"key":"8504_CR61","unstructured":"Mai, J. K., Majtanik, M. & Paxinos, G. Atlas of the Human Brain 4th edn (Academic, 2015)."},{"key":"8504_CR62","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02584-9","volume":"23","author":"S Choudhary","year":"2022","unstructured":"Choudhary, S. & Satija, R. Comparison and evaluation of statistical error models for scRNA-seq. Genome Biol. 23, 27 (2022).","journal-title":"Genome Biol."},{"key":"8504_CR63","first-page":"None","volume":"2","author":"EJ Gardner","year":"2022","unstructured":"Gardner, E. J. et al. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes. Cell Genom. 2, None (2022).","journal-title":"Cell Genom."},{"key":"8504_CR64","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).","journal-title":"Genome Biol."},{"key":"8504_CR65","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434\u2013443 (2020).","journal-title":"Nature"},{"key":"8504_CR66","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886\u2013D894 (2019).","journal-title":"Nucleic Acids Res."},{"key":"8504_CR67","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/ng.3190","volume":"47","author":"PR Loh","year":"2015","unstructured":"Loh, P. R. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 47, 284\u2013290 (2015).","journal-title":"Nat. Genet."},{"key":"8504_CR68","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","volume":"88","author":"J Yang","year":"2011","unstructured":"Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76\u201382 (2011).","journal-title":"Am. J. Hum. Genet."}],"updated-by":[{"DOI":"10.1038\/s41586-025-08826-1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000}}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-08504-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-08504-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-08504-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T09:26:31Z","timestamp":1742376391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-08504-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":68,"journal-issue":{"issue":"8055","published-print":{"date-parts":[[2025,3,20]]}},"alternative-id":["8504"],"URL":"https:\/\/doi.org\/10.1038\/s41586-024-08504-8","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,5]]},"assertion":[{"value":"20 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2025","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41586-025-08826-1","URL":"https:\/\/doi.org\/10.1038\/s41586-025-08826-1","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.L., J.P.-W., L.B.K. and C.P. are Novo Nordisk employees and\/or shareholders. J.R.B.P. is an employee and shareholder of Insmed. J.R.B.P. also receives research funding from GSK and consultancy fees from WW International. B.Y.H.L. provides remunerated consultancy for Nuntius Therapeutics. G.S.H.Y. receives grant funding from Novo Nordisk and consults for both Novo Nordisk and Eli Lilly and Company. J.C.B. is co-founder of Cerapeutix and has received research funding through collaborations with Sanofi Aventis and Novo Nordisk Inc., he also consulted for Eli Lilly and Company and Novo Nordisk, all of which did not affect the content of this article. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}