{
  "abstract": "Objective Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle. Methods Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1 -/- /γ3 -/- ) and single knockout (imγ1⁻ / ⁻ and imγ3⁻ / ⁻) mice were generated . Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed. Results snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo , glucose uptake stimulated by either AICAR or MK-8722 was abolished in imγ1⁻ / ⁻/γ3⁻ / ⁻ muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo . AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3⁻ / ⁻, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1⁻ / ⁻ mice. Conclusions While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "Dipsikha Biswas"
    },
    {
      "name": "Ever Espino-Gonzalez"
    },
    {
      "name": "Danial Ahwazi"
    },
    {
      "name": "Jordana Freemantle"
    },
    {
      "name": "Amy Ehrlich"
    },
    {
      "name": "Charline Jomard"
    },
    {
      "name": "Jonas Brorson"
    },
    {
      "name": "Agnete Schou"
    },
    {
      "name": "Jean Farup"
    },
    {
      "name": "Julien Gondin"
    },
    {
      "name": "Jesper Just"
    },
    {
      "name": "Marc Foretz"
    },
    {
      "name": "Jonas Treebak"
    },
    {
      "name": "Marianne Agerholm"
    },
    {
      "name": "Kei Sakamoto"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dv7hbfxa81ha7.bib",
  "cited_by": 5,
  "doi": "10.1016/j.molmet.2025.102294",
  "fulltext_url": null,
  "id": "dv7hbfxa81ha7",
  "issns": [
    "2212-8778"
  ],
  "landing_url": "https://hal.science/hal-05398089v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
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    [
      "hal",
      "1.sdv.bbm"
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    [
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    [
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      "1312|Metabolism, Diabetes, and Cancer"
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  "openalex": "W4416812459",
  "pdf_url": "https://hal.science/hal-05852814/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-03",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/dv7hbfxa81ha7.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:20:47Z",
      "native_id": "hal-05398089",
      "source": "hal",
      "url": "https://hal.science/hal-05398089v1"
    },
    {
      "first_seen": "2026-11-05T12:20:13Z",
      "native_id": "hal-05852814",
      "source": "hal",
      "url": "https://hal.science/hal-05852814v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "hal:2.sdv.bbm.bm",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "hal:2.sdv.mhep.em",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle",
  "title_text": "Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:20:25Z",
  "url": "https://research.draconitic.com/paper/dv7hbfxa81ha7",
  "venue": "Molecular metabolism",
  "versions": []
}