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

9 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

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