title: Zinc-α2-Glycoprotein Modulates AKT-Dependent Insulin Signaling in Human Adipocytes by Activation of the PP2A Phosphatase.
abstract: OBJECTIVE
  Evidence from mouse models suggests that zinc-α2-glycoprotein (ZAG) is a novel anti-obesity adipokine. In humans, however, data are controversial and its physiological role in adipose tissue (AT) remains unknown. Here we explored the molecular mechanisms by which ZAG regulates carbohydrate metabolism in human adipocytes.
  
  
  METHODS
  ZAG action on glucose uptake and insulin action was analyzed. β1 and β2-adrenoreceptor (AR) antagonists and siRNA targeting PP2A phosphatase were used to examine the mechanisms by which ZAG modulates insulin sensitivity. Plasma levels of ZAG were measured in a lean patient cohort stratified for HOMA-IR.
  
  
  RESULTS
  ZAG treatment increased basal glucose uptake, correlating with an increase in GLUT expression, but induced insulin resistance in adipocytes. Pretreatment of adipocytes with propranolol and a specific β1-AR antagonist demonstrated that ZAG effects on basal glucose uptake and GLUT4 expression are mediated via β1-AR, whereas inhibition of insulin action is dependent on β2-AR activation. ZAG treatment correlated with an increase in PP2A activity. Silencing of the PP2A catalytic subunit abrogated the negative effect of ZAG on insulin-stimulated AKT phosphorylation and glucose uptake but not on GLUT4 expression and basal glucose uptake. ZAG circulating levels were unchanged in a lean patient cohort stratified for HOMA-IR. Neither glucose nor insulin was associated with plasma ZAG.
  
  
  CONCLUSIONS
  ZAG inhibits insulin-induced glucose uptake in human adipocytes by impairing insulin signaling at the level of AKT in a β2-AR- and PP2A-dependent manner.
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Ceperuelo-Mallafré
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ejarque
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Duran
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Gisela
authors.initials: G
authors.lastname: Pachón
authors.affiliation: Departament of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vázquez-Carballo
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Kelly
authors.initials: K
authors.lastname: Roche
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Catalina
authors.initials: C
authors.lastname: Núñez-Roa
authors.affiliation: Hospital Universitario Virgen de la Victoria, Instituto de Investigaciones Biomédicas de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Garrido-Sánchez
authors.affiliation: Hospital Universitario Virgen de la Victoria, Instituto de Investigaciones Biomédicas de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Tinahones
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Vendrell
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D029589:Seminal Plasma Proteins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome; D000090203:Zn-Alpha-2-Glycoprotein
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; D029589:Seminal Plasma Proteins; D000090203:Zn-Alpha-2-Glycoprotein; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D005947:Glucose