{
  "abstract": "Background: Ceramides are central sphingolipid intermediates whose abundance and molecular composition are closely linked to insulin resistance. Ceramide synthases (CerSs) generate ceramides and, in several family members, also contain a conserved homeodomain with poorly understood metabolic functions. Drosophila has a single CerS, Schlank, which contains a catalytic Lag1p motif and two predicted nuclear localization sequences, NLS1 and NLS2. We investigated how distinct Schlank homeodomain mutations affect high-sugar diet (HSD)-induced insulin resistance.\n\nResults: Endogenous KINLS1 and KIE118A knock-in alleles retained DNA binding and transcriptional repression under basal conditions but increased susceptibility to HSD-induced metabolic dysfunction. Both mutants developed enhanced hyperglycemia and impaired insulin-responsive tGPH recruitment, while KIE118A additionally showed increased FoxO nuclear localization and DILP2 retention in insulin-producing cells. By contrast, fat-body-specific switching to the DNA-binding-deficient NLS2 variant or the catalytically inactive H215D variant attenuated selected HSD-induced phenotypes, including FoxO nuclear accumulation and DILP2 retention, without fully correcting hyperglycemia or reduced body weight. Lipidomic analysis revealed extensive diet-dependent sphingolipid remodeling. In particular, NLS2 and H215D markedly reduced the fat-body ceramide pool, including abundant d14:1/20:0- and d14:1/22:0-containing Cer, CerPE, and HexCer species.\n\nConclusions: The Schlank homeodomain regulates insulin homeostasis in a site- and tissue-dependent manner. Distinct homeodomain mutations can either increase susceptibility to or partially attenuate HSD-induced insulin resistance, potentially involving insulin signaling, inter-organ communication, and sphingolipid composition.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "Christian Vera-Granda"
    },
    {
      "name": "Mariangela Sociale"
    },
    {
      "name": "Konstantin Beckschäfer"
    },
    {
      "name": "Ilja Kanevskij"
    },
    {
      "name": "Merlin Gerding"
    },
    {
      "name": "Franka Eckardt"
    },
    {
      "name": "Hannah Rindsfüsser"
    },
    {
      "name": "Christoph Thiele"
    },
    {
      "name": "Anna B. Ziegler"
    },
    {
      "name": "Margret H. Bülow"
    },
    {
      "name": "Reinhard Bauer"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8bdgv864vdmhe.bib",
  "cited_by": 0,
  "doi": "10.1186/s12915-026-02763-9",
  "fulltext_url": null,
  "id": "8bdgv864vdmhe",
  "issns": [
    "1741-7007"
  ],
  "landing_url": "https://link.springer.com/article/10.1186/s12915-026-02763-9",
  "language": null,
  "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": [
    [
      "openalex",
      "1312|Sphingolipid Metabolism and Signaling"
    ]
  ],
  "openalex": "W7222685175",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-16",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/8bdgv864vdmhe.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:05Z",
      "native_id": "10.1186/s12915-026-02763-9",
      "source": "crossref",
      "url": "https://link.springer.com/article/10.1186/s12915-026-02763-9"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Sphingolipid Metabolism and Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Drosophila CerS homeodomain sites differentially alter insulin resistance",
  "title_text": "Drosophila CerS homeodomain sites differentially alter insulin resistance",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:05Z",
  "url": "https://research.draconitic.com/paper/8bdgv864vdmhe",
  "venue": "BMC Biology",
  "versions": []
}