{
  "abstract": "Lactate serves as a prognostic biomarker for sepsis, yet its adipose-centered signaling pathway driving persistent metabolic disorders remains unclear. We reveal that lactate accumulation triggers browning of white adipose tissue (WAT) via GPR81 to aggravate sepsis-induced hypermetabolism, muscle wasting, and insulin resistance. Septic patients exhibit hyperlactatemia and WAT browning, with lactate concentrations correlated with fat and muscle loss. Genetically deleting UCP1 substantially attenuates LPS-induced hypermetabolism, muscle wasting, and insulin resistance, confirming WAT browning as a major mediator of sepsis-associated metabolic disorders. Lactate supplementation and pharmacological interventions using glycolysis or lactate dehydrogenase inhibitors identify lactate as the upstream pathogenic trigger. Using siRNA screening, global GPR81 knockout, and AAV9-mediated adipose-specific GPR81 knockdown, we identify GPR81 as the lactate receptor mediating UCP1 upregulation. Mechanistically, GPR81 activation induces CTRP6 and p-p38 to upregulate UCP1. AAV9-mediated overexpression of CTRP6/MKK6 in GPR81-/- mice, together with pharmacological downregulation of CTRP6 or inhibition of p-p38, supports the involvement of this pathway in WAT browning. Taken together, evidence from clinical data, gene-knockout mice, and primary adipocyte experiments demonstrates that lactate drives WAT browning in a GPR81-dependent manner to aggravate sepsis-associated metabolic disorders, identifying potential targets for therapeutic investigation in metabolic disorders unresponsive to conventional anti-infective and nutritional support treatments.",
  "abstract_shown": true,
  "affiliations": [
    "Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China.",
    "Department of Thyroid and Breast Surgery, Suzhou Wuzhong People's Hospital, Suzhou, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Chunliang Zheng"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaohua Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Shuo Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Chungen Xing"
    },
    {
      "affs": [
        0
      ],
      "name": "Chun Cao",
      "orcid": "0000-0002-0443-6069"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8q222wrep2aph.bib",
  "cited_by": 0,
  "doi": "10.1002/advs.78487",
  "fulltext_url": "https://europepmc.org/articles/PMC13720389",
  "id": "8q222wrep2aph",
  "issns": [
    "2198-3844"
  ],
  "landing_url": "https://europepmc.org/article/MED/42958789",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2737|Adipose Tissue and Metabolism"
    ]
  ],
  "openalex": "W7224932726",
  "pdf_url": "https://europepmc.org/articles/PMC13720389?pdf=render",
  "pmcid": "PMC13720389",
  "pmid": "42958789",
  "published": "2026-10-29",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/8q222wrep2aph.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:36Z",
      "native_id": "MED:42958789",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42958789"
    },
    {
      "first_seen": "2026-11-03T12:21:16Z",
      "native_id": "PMC13720389",
      "source": "pmc",
      "url": "https://doi.org/10.1002/advs.78487"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Adipose Tissue and Metabolism",
      "subfield": "physiology"
    }
  ],
  "title": "Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.",
  "title_text": "Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:21:16Z",
  "url": "https://research.draconitic.com/paper/8q222wrep2aph",
  "venue": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)",
  "versions": []
}