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. (C) 2003 Wiley-Liss, Inc.

Serra, C., Federici, M., Buongiorno, A., Senni, M.i., Morelli, S., Segratella, E., et al. (2003). Transgenic mice with dominant negative PKC-theta in skeletal muscle: A new model of insulin resistance and obesity. JOURNAL OF CELLULAR PHYSIOLOGY [10.1002/jcp.10278].

Transgenic mice with dominant negative PKC-theta in skeletal muscle: A new model of insulin resistance and obesity

FEDERICI, MASSIMO;LAURO, RENATO;
2003-01-01

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. (C) 2003 Wiley-Liss, Inc.
2003
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITA' MOTORIE
Settore MED/09 - MEDICINA INTERNA
English
Con Impact Factor ISI
PROTEIN-KINASE-C; JURKAT T-CELLS; GLYCOGEN-SYNTHESIS; MOLECULAR-CLONING; GLUCOSE-TOLERANCE; ADIPOSE-TISSUE; FATTY-ACID; NPKC-THETA; EXPRESSION; ACTIVATION
Serra, C., Federici, M., Buongiorno, A., Senni, M.i., Morelli, S., Segratella, E., et al. (2003). Transgenic mice with dominant negative PKC-theta in skeletal muscle: A new model of insulin resistance and obesity. JOURNAL OF CELLULAR PHYSIOLOGY [10.1002/jcp.10278].
Serra, C; Federici, M; Buongiorno, A; Senni, Mi; Morelli, S; Segratella, E; Pascuccio, M; Tiveron, C; Mattei, E; Tatangelo, L; Lauro, R; Molinaro, M; Giaccari, A; Bouche, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/53521
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