title: Effect of dehydroepiandrosterone (DHEA) on Akt and protein kinase C zeta (PKCζ) phosphorylation in different tissues of C57BL6, insulin receptor substrate (IRS)1(-/-), and IRS2(-/-) male mice fed a high-fat diet.
abstract: We have previously reported that dehydroepiandrosterone (DHEA) suppresses the activity and mRNA expression of the hepatic gluconeogenic enzyme glucose-6-phosphatase (G6Pase), and hepatic glucose production in db/db mice. Tyrosine phosphorylation levels of Insulin receptor substrate (IRS)1 and IRS2 reportedly differ between the liver and muscle tissue and the effect of DHEA on insulin signaling has not been elucidated. Therefore, we examined DHEA's effect on the liver and muscle tissue of IRS1(-/-) and IRS2(-/-) mice. Eight-week-old male C57BL6, IRS1(-/-), and IRS2(-/-) mice were fed a high-fat diet (HFD), or an HFD containing 0.2% DHEA for 4 weeks. In a separate experiment, 8-week-old male C57BL6 mice were fed an HFD or an HFD containing 0.2% androstenedione for 4 weeks. In an insulin tolerance test, DHEA administration decreased the initial plasma glucose levels in the C57BL6, IRS1(-/-), and IRS2(-/-) mice but did not decrease the ratios to the basal blood glucose level. Although DHEA administration increased Akt phosphorylation in the liver of the C57BL6, IRS1(-/-), and IRS2(-/-) mice, androstenedione administration did not increase Akt phosphorylation in the liver of C57BL6 mice. DHEA administration did not increase Akt and PKCζ phosphorylation in the muscle tissue of C57BL6, IRS1(-/-), or IRS2(-/-) mice. However, androstenedione administration increased Akt and PKCζ phosphorylation in the muscle tissue of C57BL6 mice. These findings suggest that the effect of DHEA on insulin action in the liver is self-mediated by DHEA or DHEA sulfate (DHEA-S) in the presence of IRS1, IRS2, or both.
authors.affiliation: Department of Biostatistics, Yokohama City University Hospital, Japan; Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Department of Biostatistics, Yokohama City University Hospital, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguri
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan. Electronic address: terauchi@yokohama-cu.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000735:Androstenedione / Q000502:physiology; D000818:Animals; D003687:Dehydroepiandrosterone / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D000735:Androstenedione; D003687:Dehydroepiandrosterone; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse
keywords: Akt; Dehydroepiandrosterone; IRS1; IRS2; Liver