title: Transgenic mice with dominant negative PKC-theta in skeletal muscle: a new model of insulin resistance and obesity.
abstract: Protein kinase C theta (PKC-theta) is the PKC isoform predominantly expressed in skeletal muscle, and it is supposed to mediate many signals necessary for muscle histogenesis and homeostasis, such as TGFbeta, nerve-dependent signals and insulin. To study the role of PKC-theta in these mechanisms we generated transgenic mice expressing a "kinase dead" mutant form of PKC-theta (PKC-thetaK/R), working as "dominant negative," specifically in skeletal muscle. These mice are viable and fertile, however, by the 6-7 months of age, they gain weight, mainly due to visceral fat deposition. Before the onset of obesity (4 months of age), they already show increased fasting and fed insulin levels and reduced insulin-sensitivity, as measured by ipITT, but normal glucose tolerance, as measured by ipGTT. After the 6-7 months of age, transgenic mice develop hyperinsulinemia in the fasting and fed state. The ipGTT revealed in the transgenic mice both hyperglycemia and hyperinsulinemia. At the molecular level, impaired activation of the IR/IRS/PI3K pathway and a significant decrease both in the levels and in insulin-stimulated activation of the serine/threonine kinase Akt were observed. Taken together these data demonstrate that over-expression of dominant negative PKC-theta in skeletal muscle causes obesity associated to insulin resistance, as demonstrated by defective receptor and post-receptorial activation of signaling cascade.
authors.affiliation: Department of Histology and Medical Embryology, University of Rome La Sapienza, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Serra
authors.forename: M
authors.initials: M
authors.lastname: Federici
authors.forename: A
authors.initials: A
authors.lastname: Buongiorno
authors.forename: M I
authors.initials: MI
authors.lastname: Senni
authors.forename: S
authors.initials: S
authors.lastname: Morelli
authors.forename: E
authors.initials: E
authors.lastname: Segratella
authors.forename: M
authors.initials: M
authors.lastname: Pascuccio
authors.forename: C
authors.initials: C
authors.lastname: Tiveron
authors.forename: E
authors.initials: E
authors.lastname: Mattei
authors.forename: L
authors.initials: L
authors.lastname: Tatangelo
authors.forename: R
authors.initials: R
authors.lastname: Lauro
authors.forename: M
authors.initials: M
authors.lastname: Molinaro
authors.forename: A
authors.initials: A
authors.lastname: Giaccari
authors.forename: Marina
authors.initials: M
authors.lastname: Bouché
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005799:Genes, Dominant / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology*; D009154:Mutation; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D005947:Glucose