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Insulin-Mediated Phosphorylation of the Proline-Rich Akt Substrate PRAS40 Is Impaired in Insulin Target Tissues of High-Fat Diet–Fed Rats

¹ Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
² Department of Anatomy and Embryology/Central Animal Facility, Leiden University Medical Center, Leiden, the Netherlands
³ Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
⁴ Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands
⁵ Laboratory for Physiology, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands
⁶ German Diabetes Center, Institute of Clinical Biochemistry and Pathobiochemisty, Düsseldorf, Germany
⁷ Department of Endocrinology, Diabetes Center, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands

Address correspondence and reprint requests to Dr. D.M. Ouwens, Department of Molecular Cell Biology, Section of Signal Transduction and Ageing, Leiden University Medical Center, Postzone S1-P, P.O. Box 9600, NL-2300 RC Leiden, Netherlands. E-mail: d.m.ouwens{at}lumc.nl

Abbreviations: DAPI, 4',6-diamidino-2-phenylindole; ERK, extracellular signal–related kinase; GSK, glycogen synthase kinase; HFD, high-fat diet; LFD, low-fat diet; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3'-kinase; PKB, protein kinase B; PRAS40, proline-rich Akt substrate 40; TBS, Tris-buffered saline

Clinical insulin resistance is associated with decreased activation of phosphatidylinositol 3'-kinase (PI3K) and its downstream substrate protein kinase B (PKB)/Akt. However, its physiological protein substrates remain poorly characterized. In the present study, the effect of in vivo insulin action on phosphorylation of the PKB/Akt substrate 40 (PRAS40) was examined. In rat and mice, insulin stimulated PRAS40-Thr246 phosphorylation in skeletal and cardiac muscle, the liver, and adipose tissue in vivo. Physiological hyperinsulinemia increased PRAS40-Thr246 phosphorylation in human skeletal muscle biopsies. In cultured cell lines, insulin-mediated PRAS40 phosphorylation was prevented by the PI3K inhibitors wortmannin and LY294002. Immunohistochemical and immunofluorescence studies showed that phosphorylated PRAS40 is predominantly localized to the nucleus. Finally, in rats fed a high-fat diet (HFD), phosphorylation of PRAS40 was markedly reduced compared with low-fat diet–fed animals in all tissues examined. In conclusion, the current study identifies PRAS40 as a physiological target of in vivo insulin action. Phosphorylation of PRAS40 is increased by insulin in human, rat, and mouse insulin target tissues. In rats, this response is reduced under conditions of HFD-induced insulin resistance.

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