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Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.

Panariello F, Perruolo G, Cassese A, Giacco F, Botta G, Barbagallo AP, Muscettola G, Beguinot F, Formisano P, de Bartolomeis A - J. Cell. Physiol. (2012)

Bottom Line: Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively.Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%.Insulin-stimulated Akt phosphorylation was also reduced by about 40%.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Neuroscienze, Sezione di Psichiatria, Laboratorio di Psichiatria Molecolare, University of Napoli Federico II, Napoli, Italy.

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Clozapine effect in caudate–putamen, cortex, and tibialis muscle. Two groups of eight mice were treated once a day for 21 days with single injection of saline, and clozapine (10 mg/kg). A: Phospho-Ser-473 Akt (pAkt), (B) Ped/Pea-15, and (C) phospho-PKC-ζ (p-PKC-ζ) levels were measured in caudate–putamen (CP), cortex, and tibialis muscle, 30 min after the last injection of clozapine or saline. Equal loading of the samples was ensured by control blot with antiactin antibodies. Phosphorylated Akt and PKC-ζ were expressed as ratio with total Akt and total PKC-ζ levels, Ped/Pea-15 as arbitrary units derived from densitometric analysis. All values were further normalized on actin values. Significant differences compared to the respective saline-treated control have been indicated by asterisks, **P < 0.01, ***P < 0.001.
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fig08: Clozapine effect in caudate–putamen, cortex, and tibialis muscle. Two groups of eight mice were treated once a day for 21 days with single injection of saline, and clozapine (10 mg/kg). A: Phospho-Ser-473 Akt (pAkt), (B) Ped/Pea-15, and (C) phospho-PKC-ζ (p-PKC-ζ) levels were measured in caudate–putamen (CP), cortex, and tibialis muscle, 30 min after the last injection of clozapine or saline. Equal loading of the samples was ensured by control blot with antiactin antibodies. Phosphorylated Akt and PKC-ζ were expressed as ratio with total Akt and total PKC-ζ levels, Ped/Pea-15 as arbitrary units derived from densitometric analysis. All values were further normalized on actin values. Significant differences compared to the respective saline-treated control have been indicated by asterisks, **P < 0.01, ***P < 0.001.

Mentions: Protein extracts from CP and cortex were obtained and assayed by Western blot with specific antibodies. In the animals treated with clozapine, increased levels of phosphorylated Akt were detected in CP (Fig. 8A), but not in cortex. This was paralleled by increased Ped/Pea-15 detection (Fig. 8B) and reduced PKC-ζ phosphorylation in CP (Fig. 8C). Again, no difference was detected in cortex of the treated animals.


Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.

Panariello F, Perruolo G, Cassese A, Giacco F, Botta G, Barbagallo AP, Muscettola G, Beguinot F, Formisano P, de Bartolomeis A - J. Cell. Physiol. (2012)

Clozapine effect in caudate–putamen, cortex, and tibialis muscle. Two groups of eight mice were treated once a day for 21 days with single injection of saline, and clozapine (10 mg/kg). A: Phospho-Ser-473 Akt (pAkt), (B) Ped/Pea-15, and (C) phospho-PKC-ζ (p-PKC-ζ) levels were measured in caudate–putamen (CP), cortex, and tibialis muscle, 30 min after the last injection of clozapine or saline. Equal loading of the samples was ensured by control blot with antiactin antibodies. Phosphorylated Akt and PKC-ζ were expressed as ratio with total Akt and total PKC-ζ levels, Ped/Pea-15 as arbitrary units derived from densitometric analysis. All values were further normalized on actin values. Significant differences compared to the respective saline-treated control have been indicated by asterisks, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306790&req=5

fig08: Clozapine effect in caudate–putamen, cortex, and tibialis muscle. Two groups of eight mice were treated once a day for 21 days with single injection of saline, and clozapine (10 mg/kg). A: Phospho-Ser-473 Akt (pAkt), (B) Ped/Pea-15, and (C) phospho-PKC-ζ (p-PKC-ζ) levels were measured in caudate–putamen (CP), cortex, and tibialis muscle, 30 min after the last injection of clozapine or saline. Equal loading of the samples was ensured by control blot with antiactin antibodies. Phosphorylated Akt and PKC-ζ were expressed as ratio with total Akt and total PKC-ζ levels, Ped/Pea-15 as arbitrary units derived from densitometric analysis. All values were further normalized on actin values. Significant differences compared to the respective saline-treated control have been indicated by asterisks, **P < 0.01, ***P < 0.001.
Mentions: Protein extracts from CP and cortex were obtained and assayed by Western blot with specific antibodies. In the animals treated with clozapine, increased levels of phosphorylated Akt were detected in CP (Fig. 8A), but not in cortex. This was paralleled by increased Ped/Pea-15 detection (Fig. 8B) and reduced PKC-ζ phosphorylation in CP (Fig. 8C). Again, no difference was detected in cortex of the treated animals.

Bottom Line: Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively.Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%.Insulin-stimulated Akt phosphorylation was also reduced by about 40%.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Neuroscienze, Sezione di Psichiatria, Laboratorio di Psichiatria Molecolare, University of Napoli Federico II, Napoli, Italy.

Show MeSH
Related in: MedlinePlus