title: Akt mediates the cross-talk between beta-adrenergic and insulin receptors in neonatal cardiomyocytes.
abstract: Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance. Although the heart is a target organ of insulin, few studies have examined the mechanisms by which beta-adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between beta adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that beta-adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca2+-dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulation of beta-adrenergic receptors inhibits both insulin-stimulated glucose uptake and insulin-induced autophosphorylation of the insulin receptor, and at the same time promotes threonine phosphorylation of the insulin receptor. This is mediated by serine 473 phosphorylation of Akt through PKA/Ca2+ and PI3K-dependent pathways. Under basal conditions, E40K Tg mice show increased levels of threonine phosphorylation of the beta subunit of the insulin receptor and blunted tyrosine autophosphorylation of the beta-subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, beta-adrenergic receptor stimulation impairs insulin signaling transduction machinery through an Akt-dependent pathway, suggesting that Akt is critically involved in the regulation of insulin sensitivity.
authors.affiliation: Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Morisco
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bellis
authors.forename: Chiara
authors.initials: C
authors.lastname: Marrone
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000633:toxicity; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D007333:Insulin Resistance / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D010769:Phosphothreonine / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D013564:Sympathetic Nervous System / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D017868:Cyclic AMP-Dependent Protein Kinases; D003847:Deoxyglucose; D007545:Isoproterenol; D019869:Phosphatidylinositol 3-Kinases; D010768:Phosphoserine; D010769:Phosphothreonine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D011943:Receptors, Adrenergic, beta; C494920:Akt1 protein, rat