title: Prep1 deficiency induces protection from diabetes and increased insulin sensitivity through a p160-mediated mechanism.
abstract: We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1(i/i)) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1(i/i) muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1alpha, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1(i/i) mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via Sergio Pansini, 5, Naples 80131, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Luis Cesar
authors.initials: LC
authors.lastname: Fernandez Diaz
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.forename: Salvatore
authors.initials: S
authors.lastname: Iovino
authors.forename: Silvia
authors.initials: S
authors.lastname: Mori
authors.forename: Victor Manuel
authors.initials: VM
authors.lastname: Diaz
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.forename: Angela
authors.initials: A
authors.lastname: Cassese
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D018398:Homeodomain Proteins; D007328:Insulin; C110421:Mybbp1a protein, mouse; D009687:Nuclear Proteins; C481797:Pbx1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C491412:Pknox1 protein, mouse; C485290:Ppargc1a protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D016601:RNA-Binding Proteins; C495693:Slc2a4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005934:Glucagon