{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:59:18Z","timestamp":1785401958534,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Molecular Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["8045-00091B"],"award-info":[{"award-number":["8045-00091B"]}],"id":[{"id":"https:\/\/ror.org\/02sptwz63","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 DK124238"],"award-info":[{"award-number":["R01 DK124238"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK56731"],"award-info":[{"award-number":["R01DK56731"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30DK020572"],"award-info":[{"award-number":["P30DK020572"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NNF23SA0084103"],"award-info":[{"award-number":["NNF23SA0084103"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NNF18CC0034900"],"award-info":[{"award-number":["NNF18CC0034900"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Despite widespread loss of leptin responsiveness in obesity, endogenous leptin continues to restrain feeding, yet the neural substrates that remain sensitive and mediate this effect are unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we show that while most hypothalamic leptin receptor (\n                  <jats:italic>Lepr<\/jats:italic>\n                  ) neurons minimally respond to elevated leptin, a single population defined by glucagon-like peptide-1 receptor (\n                  <jats:italic>Glp1r<\/jats:italic>\n                  ) co-expression retains robust leptin sensitivity. These\n                  <jats:italic>Lepr\/Glp1r<\/jats:italic>\n                  neurons project onto and restrain orexigenic\n                  <jats:italic>Agrp<\/jats:italic>\n                  neurons.\n                  <jats:italic>Lepr<\/jats:italic>\n                  deletion from\n                  <jats:italic>Lepr\/Glp1r<\/jats:italic>\n                  neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation- a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin action through a single neuronal population governs downstream circuit activity to limit hyperphagia and weight gain during obesity.\n                <\/jats:p>","DOI":"10.64898\/2026.03.26.714161","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T21:35:11Z","timestamp":1774906511000},"source":"Crossref","is-referenced-by-count":0,"title":["A uniquely leptin sensitive hypothalamic neuron population limits hyperphagia and weight gain in diet-induced obesity"],"prefix":"10.64898","author":[{"given":"Dylan M","family":"Belmont-Rausch","sequence":"first","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"},{"name":"Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedicte Schultz","family":"Kapel","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail J.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI"},{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ding","sequence":"additional","affiliation":[{"name":"Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany"},{"name":"Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M.","family":"Duensing","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI"},{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Coester","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilie Vad","family":"Mathiesen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Cabot","sequence":"additional","affiliation":[{"name":"Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany"},{"name":"Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny M.","family":"Brown","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte H\u00f8y","family":"Kruse","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"},{"name":"Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoffer","family":"Clemmensen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington at South Lake Union, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Fenselau","sequence":"additional","affiliation":[{"name":"Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany"},{"name":"Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"},{"name":"Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, 50924 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9468-2046","authenticated-orcid":false,"suffix":"Jr","given":"Martin G.","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI"},{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0207-4831","authenticated-orcid":false,"given":"Tune H","family":"Pers","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark"},{"name":"Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, 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