@article{ebae90536bf5452c81acff6197b88153,
title = "Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles",
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.",
author = "Clair Crewe and Shiuhwei Chen and Dawei Bu and Gliniak, {Christy M.} and Asterholm, {Ingrid Wernstedt} and Yu, {Xin Xin} and Nolwenn Joffin and {de Souza}, {Camila O.} and Funcke, {Jan Bernd} and Oh, {Da Young} and Oleg Varlamov and Robino, {Jacob J.} and Ruth Gordillo and Scherer, {Philipp E.}",
note = "Funding Information: Acknowledgments. The authors thank the UT Southwestern Metabolic Phenotyping Core for help and Charlotte E. Lee of UT Southwestern for assistance in embedding and processing of histological samples and the UT Southwestern Electron Microscopy Core for help in sample processing for electron microscopy. The authors also thank Shimadzu Scientific Instruments for the collaborative efforts in mass spectrometry technology resources. Funding. This study was supported by National Institutes of Health (NIH) grants R01-DK55758, R01-DK127274, R01-DK099110, R01-DK131537, and RC2-DK118620 (to P.E.S.). C.C. is supported by K99-DK122019 and R00-DK122019. C.M.G. is supported by NIH grant F32-DK122623. D.Y.O. is supported by NIH grant R01-DK108773. I.W.A. is supported by Swedish Research Council grants 2013-07107, 2017-00792, and 2020-01463; Swedish Diabetes Foundation grant DIA2019-419; Novo Nordisk Foundation grant NNF19OC0056601, and Diabetes Research & Wellness Foundation grant 2334. O.V. and J.J.R. are supported by NIH grants P51-OD01192 for operation of the Oregon National Primate Research Center and 1S10-OD025002-01. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.C. conducted all experiments except for those listed below. C.C. and P.E.S designed the studies, analyzed and interpreted data, and wrote the manuscript. S.C. conducted islet isolations and the in vitro GSIS assay with islets. S.C. and X.X.Y. performed the radioactive glucose uptake experiments. D.B. conducted histological staining. C.M.G. and N.J. assisted in mouse experiments, tissue harvesting, and processing. I.W.A. and D.Y.O. contributed valuable resources and key insight. C.O.d.S. performed the experiments with MIN6 cells. J.-B.F. helped with electron microscopy experiments. O.V. and J.J.R. conducted the histological image analysis. R.G. performed the TCA intermediate measurements and analysis and, along with the metabolic core, conducted tissue triglyceride measurements, metabolic Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association.",
year = "2022",
month = dec,
doi = "10.2337/db22-0035",
language = "English (US)",
volume = "71",
pages = "2496--2512",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "12",
}