{
  "abstract": "Chronic nutrient excess drives adipose tissue fibrosis and inflammation, key features of metabolic dysfunction that underlie insulin resistance and Type 2 diabetes. However, the molecular mechanisms linking hyperglycemia to pathological adipose tissue remodeling remain less understood. Here, we identify a post-translational mechanism by which high glucose destabilizes PRDM16, a key transcriptional regulator of adipose tissue identity, through O-GlcNAcylation of its E3 ligase adaptor protein, amyloid beta precursor protein binding protein 2 (APPBP2). Glucose-induced O-GlcNAcylation of APPBP2 at S561 promotes its interaction with PRDM16, triggering PRDM16 ubiquitination and proteasomal degradation. Notably, APPBP2S561N is a hypomorphic variant identified in human populations who exhibit improved glucose homeostasis. Knock-in mice harboring APPBP2S561N maintained elevated PRDM16 protein levels independently of mRNA abundance and are protected against diet-induced adipose tissue fibrosis, inflammation, glucose intolerance, and insulin resistance. These metabolic benefits are independent of UCP1-mediated thermogenesis, as metabolic protection of APPBP2S561N persists in the Ucp1 null background. These findings reveal a glucose-responsive O-GlcNAc pathway that couples nutrient excess to adipose tissue dysfunction through post-translational regulation of PRDM16 protein stability.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "Shingo Kajimura",
      "orcid": "0000-0003-0672-5910"
    },
    {
      "name": "Yong Chen",
      "orcid": "0000-0002-0723-8105"
    },
    {
      "name": "Li Chen"
    },
    {
      "name": "Yusuke Higuchi"
    },
    {
      "name": "Daisuke Kato"
    },
    {
      "name": "Qiang Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c0sw7phwsyjct.bib",
  "cited_by": 0,
  "doi": "10.21203/rs.3.rs-11471586/v1",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13734277/",
  "id": "c0sw7phwsyjct",
  "issns": [
    "2693-5015"
  ],
  "landing_url": "https://doi.org/10.21203/rs.3.rs-11471586/v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2737|Adipose Tissue and Metabolism"
    ]
  ],
  "openalex": "W7224888203",
  "pdf_url": "https://www.researchsquare.com/article/rs-11471586/latest.pdf",
  "pmcid": "PMC13734277",
  "pmid": "42990537",
  "published": "2026-10-30",
  "publisher": "American Journal Experts",
  "ris": "https://research.draconitic.com/paper/c0sw7phwsyjct.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:23:53Z",
      "native_id": "PMC13734277",
      "source": "pmc",
      "url": "https://doi.org/10.21203/rs.3.rs-11471586/v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Adipose Tissue and Metabolism",
      "subfield": "physiology"
    }
  ],
  "title": "High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis",
  "title_text": "High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:53Z",
  "url": "https://research.draconitic.com/paper/c0sw7phwsyjct",
  "venue": "Research Square",
  "versions": []
}