Mechanisms of skeletal muscle insulin resistance in the CTP:phosphoethanolamine cytidylyltransferase-deficient mouse

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Chiswell, Kathryn

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University of Guelph

Abstract

The PE-Kennedy pathway gives rise to phosphatidylethanolamine (PE), which is an essential inner-membrane phospholipid. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) catalyzes the rate-limiting step that produces CDPethanolamine. CDP-ethanolamine is then combined with diacylglycerol (DAG) to produce PE in the final step. In 2007, the Pcyt2 gene was partially deleted in mice, which caused reduced flux through the Kennedy pathway and lead to the accumulation of DAG and other intermediates. The heterozygous mice exhibit elevated DAG content, hypertriglyceridemia, reduced whole-body insulin sensitivity, and impaired glucose utilization. It is well-understood that DAG accumulation leads to insulin resistance and has consistently been associated with increased PKC activation and reduced IRS1, Akt and PI3K functions. The JNK pathway has also been implicated to induce insulin resistance through IRS1-Ser307 phosphorylation. The aim of this study was to define the molecular dysregulation causing reduced insulin sensitivity in Pcyt2+/- skeletal muscle by assessing the protein expression and phosphorylation of IRS1, PI3K, Akt, GLUT4 and JNK1/2. Pcyt2 +/- muscle displays dysregulated IRS1 function under basal and insulin-stimulated conditions, decreased insulin-stimulated Akt activity, and chronically reduced PI3K protein expression. GLUT4 protein content is elevated under basal conditions and exhibits an impaired post-transcriptional response to insulin. Furthermore, insulin is associated with JNK1 and JNK2 activation in Pcyt2+/- muscle, which coincides with the observed increase in insulin-stimulated IRS1-Ser307 phosphorylation. It was concluded that Pcyt2 deficiency brings about diminished IRS1-mediated signaling in part through the JNK pathway, and this disruption ultimately leads to the development of dysregulated insulin signaling in Pcyt2-deficient mice.

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Keywords

PE-Kennedy pathway, phosphatidylethanolamine, immunoprecipitation, immunoblotting, IRSI, Akt, PI3K|JNKl, JNK2, GLUT4, protein expression, protein content, phosphorylation, protein loading

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