Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles

Clair Crewe, Shiuhwei Chen, Dawei Bu, Christy M. Gliniak, Ingrid Wernstedt Asterholm, Xin Xin Yu, Nolwenn Joffin, Camila O. de Souza, Jan Bernd Funcke, Da Young Oh, Oleg Varlamov, Jacob J. Robino, Ruth Gordillo, Philipp E. Scherer

    Research output: Contribution to journalArticlepeer-review

    1 Scopus citations

    Abstract

    Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previ-ously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adi-pocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveo-lar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Further-more, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interest-ingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of neg-ative phenotypes to other organs by EVs.

    Original languageEnglish (US)
    Pages (from-to)2496-2512
    Number of pages17
    JournalDiabetes
    Volume71
    Issue number12
    DOIs
    StatePublished - Dec 2022

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

    Fingerprint

    Dive into the research topics of 'Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles'. Together they form a unique fingerprint.

    Cite this