{
  "abstract": "Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we here show that while most hypothalamic leptin receptor (Lepr)-positive neurons minimally respond to elevated leptin, a single subpopulation defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr+/Glp1r+ neurons project onto and inhibit orexigenic Agrp neurons. Lepr deletion from Lepr+/Glp1r+ 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 responses by a single neuronal population in the hypothalamus limit hyperphagia and weight gain, among other responses, during obesity.",
  "abstract_shown": true,
  "affiliations": [
    "Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark",
    "Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA USA",
    "Present Address: Research and Development, Novo Nordisk A/S, Måløv, Denmark",
    "Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI USA",
    "Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA",
    "Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, Cologne, Germany",
    "Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany",
    "Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington at South Lake Union, Seattle, WA USA",
    "Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Dylan M Belmont-Rausch"
    },
    {
      "affs": [
        0
      ],
      "name": "Benedicte Schultz Kapel"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Abigail J Tomlinson"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Chao Ding"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Allison M Duensing"
    },
    {
      "affs": [
        0
      ],
      "name": "Bernd Coester"
    },
    {
      "affs": [
        0
      ],
      "name": "Cecilie Vad Mathiesen"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Leonie Cabot"
    },
    {
      "affs": [
        0
      ],
      "name": "Jenny M Brown",
      "orcid": "0000-0002-5072-4491"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Charlotte Høy Kruse",
      "orcid": "0009-0005-5147-9984"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shad Hassan"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Elizabeth Heaton"
    },
    {
      "affs": [
        0
      ],
      "name": "Christoffer Clemmensen",
      "orcid": "0000-0003-2456-9667"
    },
    {
      "affs": [
        7
      ],
      "name": "Michael W Schwartz"
    },
    {
      "affs": [
        5,
        6,
        8
      ],
      "name": "Henning Fenselau",
      "orcid": "0000-0001-7136-9751"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Martin G Myers",
      "orcid": "0000-0001-9468-2046"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tune H Pers",
      "orcid": "0000-0003-0207-4831"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ay444kqy9zrgf.bib",
  "cited_by": 0,
  "doi": "10.1038/s44318-026-00914-w",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13728182/",
  "id": "ay444kqy9zrgf",
  "issns": [
    "0261-4189",
    "1460-2075"
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  "landing_url": "https://doi.org/10.1038/s44318-026-00914-w",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
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  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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      "2807|Regulation of Appetite and Obesity"
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  "pmcid": "PMC13728182",
  "pmid": "42827204",
  "published": "2026-10-01",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/ay444kqy9zrgf.ris",
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      "field": "medicine",
      "origin": "openalex:2807|Regulation of Appetite and Obesity",
      "subfield": "physiology"
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  ],
  "title": "Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity",
  "title_text": "Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T14:21:13Z",
  "url": "https://research.draconitic.com/paper/ay444kqy9zrgf",
  "venue": "The EMBO Journal",
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}