title: Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15.
abstract: Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1). Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4) restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15) by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance.
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali, Università di Napoli Federico II and Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cassese
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Raciti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.forename: Luca
authors.initials: L
authors.lastname: Ulianich
authors.forename: Ilenia
authors.initials: I
authors.lastname: Castanò
authors.forename: Vittoria
authors.initials: V
authors.lastname: D'Esposito
authors.forename: Daniela
authors.initials: D
authors.lastname: Terracciano
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D010739:Phospholipase D / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019076:Transgenes; D000099221:Protein Kinase C zeta
chemical_list: D051017:Apoptosis Regulatory Proteins; D005947:Glucose; D007328:Insulin; D010739:Phospholipase D; D010750:Phosphoproteins; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000099221:Protein Kinase C zeta; C490444:Pea15 protein, mouse; C106801:phospholipase D1