title: The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis.
abstract: BACKGROUND
  We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.
  
  
  RESULTS
  We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.
  
  
  CONCLUSIONS
  These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Catanzaro, Italy. echiefari@libero.it
authors.forename: Eusebio
authors.initials: E
authors.lastname: Chiefari
authors.forename: Francesco
authors.initials: F
authors.lastname: Paonessa
authors.forename: Stefania
authors.initials: S
authors.lastname: Iiritano
authors.forename: Ilaria
authors.initials: I
authors.lastname: Le Pera
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Brunetti
authors.forename: Angelo
authors.initials: A
authors.lastname: Lupo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Foti
authors.forename: Elio
authors.initials: E
authors.lastname: Gulletta
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Antonio
authors.initials: A
authors.lastname: Brunetti
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D025741:HMGA1a Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D012333:RNA, Messenger; C502487:Rbp4 protein, mouse; D011994:Recombinant Proteins; D054839:Retinol-Binding Proteins, Plasma; D025741:HMGA1a Protein; D005934:Glucagon; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose