title: Hypoxia inhibits Cavin-1 and Cavin-2 expression and down-regulates caveolae in adipocytes.
abstract: During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.
authors.affiliation: INSERM Unité 1065 (C.R., K.D., F.P., Y.L.M.-B., J.-F.T., M.C., S.G.-P.), C3M, Mediterranean Research Centre for Molecular Medicine, Team 7 (Cellular and Molecular Physiopathology of Obesity and Diabetes), Unité de Formation et de Recherche (UFR) Medicine (C.R., K.D., F.P., P.P., S.B., Y.L.M.-B., A.T., P.G., J.-F.T., M.C., S.G.-P.), and INSERM Unité 1065 (S.B., A.T., P.G.), C3M, Mediterranean Research Centre for Molecular Medicine, Team 8 (Hepatic Complications in Obesity),University of Nice, Sophia Antipolis F-06204 Nice, France; Centre Commun de Microscopie Appliquée (S.L.-G.), University of Nice, Sophia Antipolis, UFR Sciences, Parc Valrose, F-06108 Nice, France; Unité Mixte de Recherche Centre National de la Recherche Scientifique 7277 (P.P.), Unité Mixte de Recherche INSERM Unité 1091, UFR Medicine, F-06107 Nice, France; Centre Hospitalier Universitaire de Nice, Digestive Center (S.B., A.T.), Nice F-06202, Cedex 3, France; INSERM Unité Mixte de Recherche S872 (I.D.), Centre de Recherche des Cordeliers, Eq8, F-75006 Paris, France; INSERM Unité 1063 (S.L.L.), Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, F-49933 Angers, France; and INSERM Unité Mixte de Recherche 1048 (P.V.), Institut des Maladies Métaboliques et Cardiovasculaires, Université Paul Sabatier, F-31432 Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Regazzetti
authors.forename: Karine
authors.initials: K
authors.lastname: Dumas
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: Faustine
authors.initials: F
authors.lastname: Pastor
authors.forename: Pascal
authors.initials: P
authors.lastname: Peraldi
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonnafous
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dugail
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Lay
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti-Peraldi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D021941:Caveolae / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity; D010100:Oxygen / Q000494:pharmacology*; D028044:Phosphate-Binding Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497835:CAVIN1 protein, human; C112303:CAVIN2 protein, human; D002352:Carrier Proteins; C112745:Cavin1 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D028044:Phosphate-Binding Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C000597015:Cavin2 protein, mouse; D010100:Oxygen