Akt-dependent phosphorylation of hepatic FoxO1 is compartmentalized on a WD40/Propeller/FYVE scaffold and is selectively inhibited atypical PKC in early phases of diet-induced obesity. A mechanism for impairing gluconeogenic but not lipogenic enzyme expression.

  1. Robert V. Farese
  1. Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, Florida; and the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida.
  1. Corresponding Author: Robert V. Farese, Email: rfarese{at}health.usf.edu

Abstract

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 PKC (aPKC) in liver and muscle, and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF mice, resting/basal and insulin-stimulated Akt and atypical PKC (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, which reportedly facilitates FoxO1 phosphorylation. In contrast, aPKC activity associated with WD40/Propeller/FYVE was increased. Moreover, inhibition of hepatic aPKC reduced its association with WD40/Propeller/FYVE, restored WD40/Propeller/FYVE-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 co-compartmentalized aPKC.

  • Received December 10, 2013.
  • Accepted March 31, 2014.

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