Acute reversal of lipid-induced muscle insulin resistance is associated with rapid alteration in PKC-θ localization

Abstract

Muscle insulin resistance in the chronic high-fat-fed rat is associated with increased membrane translocation and activation of the novel, lipid-responsive, protein kinase C (nPKC) isozymes PKC-θ and -ɛ. Surprisingly, fat-induced insulin resistance can be readily reversed by one high-glucose low-fat meal, but the underlying mechanism is unclear. Here, we have used this model to determine whether changes in the translocation of PKC-θ and -ɛ are associated with the acute reversal of insulin resistance. We measured cytosol and particulate PKC-α and nPKC-θ and -ɛ in muscle in control chow-fed Wistar rats (C) and 3-wk high-fat-fed rats with (HF-G) or without (HF-F) a single high-glucose meal. PKC-θ and -ɛ were translocated to the membrane in muscle of insulin-resistant HF-F rats. However, only membrane PKC-θ was reduced to the level of chow-fed controls when insulin resistance was reversed in HF-G rats [% PKC-θ at membrane, 23.0 ± 4.4% (C); 39.7 ± 3.4% (HF-F, P < 0.01 vs. C); 22.5 ± 2.7% (HF-G, P < 0.01 vs. HF-F), by ANOVA]. We conclude that, although muscle localization of both PKC-ɛ and PKC-θ are influenced by chronic dietary lipid oversupply, PKC-ɛ and PKC-θ localization are differentially influenced by acute withdrawal of dietary lipid. These results provide further support for an association between PKC-θ muscle cellular localization and lipid-induced muscle insulin resistance and stress the labile nature of high-fat diet-induced insulin resistance in the rat.