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Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity

Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical protein kinase C (aPKC) in liver and muscle and hepatic enzyme expression in mice consuming a moderate high-fat (HF)...

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Autores principales: Sajan, Mini P., Acevedo-Duncan, Mildred E., Standaert, Mary L., Ivey, Robert A., Lee, Mackenzie, Farese, Robert V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113067/
https://www.ncbi.nlm.nih.gov/pubmed/24705403
http://dx.doi.org/10.2337/db13-1863
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author Sajan, Mini P.
Acevedo-Duncan, Mildred E.
Standaert, Mary L.
Ivey, Robert A.
Lee, Mackenzie
Farese, Robert V.
author_facet Sajan, Mini P.
Acevedo-Duncan, Mildred E.
Standaert, Mary L.
Ivey, Robert A.
Lee, Mackenzie
Farese, Robert V.
author_sort Sajan, Mini P.
collection PubMed
description Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical protein kinase C (aPKC) in liver and muscle and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF diet–fed mice, resting/basal and insulin-stimulated Akt and aPKC activities were diminished in muscle, but in liver, these activities were elevated basally and were increased by insulin to normal levels. Despite elevated hepatic Akt activity, FoxO1 phosphorylation, which diminishes gluconeogenesis, was impaired; in contrast, Akt-dependent phosphorylation of glycogenic GSK3β and lipogenic mTOR was elevated. Diminished Akt-dependent FoxO1 phosphorylation was associated with reduced Akt activity associated with scaffold protein WD40/Propeller/FYVE (WD40/ProF), which reportedly facilitates FoxO1 phosphorylation. In contrast, aPKC activity associated with WD40/ProF was increased. Moreover, inhibition of hepatic aPKC reduced its association with WD40/ProF, restored WD40/ProF-associated Akt activity, restored FoxO1 phosphorylation, and corrected excessive expression of hepatic gluconeogenic and lipogenic enzymes. Additionally, Akt and aPKC activities in muscle improved, as did glucose intolerance, weight gain, hepatosteatosis, and hyperlipidemia. We conclude that Akt-dependent FoxO1 phosphorylation occurs on the WD/Propeller/FYVE scaffold in liver and is selectively inhibited in early DIO by diet-induced increases in activity of cocompartmentalized aPKC.
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spelling pubmed-41130672015-08-01 Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity Sajan, Mini P. Acevedo-Duncan, Mildred E. Standaert, Mary L. Ivey, Robert A. Lee, Mackenzie Farese, Robert V. Diabetes Signal Transduction Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical protein kinase C (aPKC) in liver and muscle and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF diet–fed mice, resting/basal and insulin-stimulated Akt and aPKC activities were diminished in muscle, but in liver, these activities were elevated basally and were increased by insulin to normal levels. Despite elevated hepatic Akt activity, FoxO1 phosphorylation, which diminishes gluconeogenesis, was impaired; in contrast, Akt-dependent phosphorylation of glycogenic GSK3β and lipogenic mTOR was elevated. Diminished Akt-dependent FoxO1 phosphorylation was associated with reduced Akt activity associated with scaffold protein WD40/Propeller/FYVE (WD40/ProF), which reportedly facilitates FoxO1 phosphorylation. In contrast, aPKC activity associated with WD40/ProF was increased. Moreover, inhibition of hepatic aPKC reduced its association with WD40/ProF, restored WD40/ProF-associated Akt activity, restored FoxO1 phosphorylation, and corrected excessive expression of hepatic gluconeogenic and lipogenic enzymes. Additionally, Akt and aPKC activities in muscle improved, as did glucose intolerance, weight gain, hepatosteatosis, and hyperlipidemia. We conclude that Akt-dependent FoxO1 phosphorylation occurs on the WD/Propeller/FYVE scaffold in liver and is selectively inhibited in early DIO by diet-induced increases in activity of cocompartmentalized aPKC. American Diabetes Association 2014-08 2014-07-17 /pmc/articles/PMC4113067/ /pubmed/24705403 http://dx.doi.org/10.2337/db13-1863 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Signal Transduction
Sajan, Mini P.
Acevedo-Duncan, Mildred E.
Standaert, Mary L.
Ivey, Robert A.
Lee, Mackenzie
Farese, Robert V.
Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title_full Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title_fullStr Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title_full_unstemmed Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title_short Akt-Dependent Phosphorylation of Hepatic FoxO1 Is Compartmentalized on a WD40/ProF Scaffold and Is Selectively Inhibited by aPKC in Early Phases of Diet-Induced Obesity
title_sort akt-dependent phosphorylation of hepatic foxo1 is compartmentalized on a wd40/prof scaffold and is selectively inhibited by apkc in early phases of diet-induced obesity
topic Signal Transduction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113067/
https://www.ncbi.nlm.nih.gov/pubmed/24705403
http://dx.doi.org/10.2337/db13-1863
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