| 1. |
- Garrido, Pablo, et al.
(author)
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Negative regulation of glucose metabolism in human myotubes by supraphysiological doses of 17 beta-estradiol or testosterone
- 2014
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In: Metabolism. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 63:9, s. 1178-1187
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Journal article (peer-reviewed)abstract
- Objective. Exposure of skeletal muscle to high levels of testosterone or estrogen induces insulin resistance, but evidence regarding the direct role of either sex hormone on metabolism is limited. Therefore, the aim of this study was to investigate the direct effect of acute sex hormone exposure on glucose metabolism in skeletal muscle. Materials/Methods. Differentiated human skeletal myotubes were exposed to either 17 beta-estradiol or testosterone and metabolic characteristics were assessed. Glucose incorporation into glycogen, glucose oxidation, palmitate oxidation, and phosphorylation of key signaling proteins were determined. Results. Treatment of myotubes with either 17 beta-estradiol or testosterone decreased glucose incorporation into glycogen. Exposure of myotubes to 17 beta-estradiol reduced glucose oxidation under basal and insulin-stimulated conditions. However, testosterone treatment enhanced basal palmitate oxidation and prevented insulin action on glucose and palmitate oxidation. Acute stimulation of myotubes with testosterone reduced phosphorylation of S6K1 and p38 MAPK. Exposure of myotubes to either 17 beta-estradiol or testosterone augmented phosphorylation GSK3 beta(ser9) and PKC delta(Thr505), two negative regulators of glycogen synthesis. Treatment of myotubes with a PKC specific inhibitor (GFX) restored the effect of either sex hormone on glycogen synthesis. PKC delta silencing restored glucose incorporation into glycogen to baseline in response to 17 beta-estradiol, but not testosterone treatment. Conclusion. An acute exposure to supraphysiological doses of either 17 beta-estradiol or testosterone regulates glucose metabolism, possibly via PKC signaling pathways. Furthermore, testosterone treatment elicits additional alterations in serine/threonine kinase signaling, including the ribosomal protein S6K1 and p38 MAPK.
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| 2. |
- Salehzadeh, Firoozeh
(author)
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The role of steroid hormones in skeletal muscle metabolism
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Steroid hormones play important roles in the regulation of whole body metabolism. Skeletal muscle is an insulin-responsive organ with a key role in overall substrate metabolism. Disturbances in skeletal muscle metabolism, as a result of hormonal imbalance may be an underlying defect in metabolic disease. Reduced insulin-responsive glucose disposal in skeletal muscle is a characteristic feature of metabolic syndrome. The overall aim of this thesis work is to identify the role of steroid hormones on glucose and lipid metabolism; and to dissect the impact of sex steroid hormones on insulin signaling pathways in human skeletal muscle. A further goal is to understand how sex differences impact on skeletal muscle metabolism. Whole body metabolism differs between men and women, and sex-dependent differences in gene expression are evident in skeletal muscle biopsies. Some sex- dependent differences in gene expression are retained in vitro in cultured human skeletal muscle. In contrast, glucose and lipid metabolism did not show any sex- dependent differences. Chronic exposure of muscle cell cultures to physiological doses of testosterone or 17 β-estradiol resulted in sex-dependent responses. Exposure to testosterone enhanced palmitate oxidation, AMP dependent protein kinase phosphorylation and IRS2 gene expression in myotubes from both sexes, while 17 β-estradiol exposure increased palmitate oxidation in myotubes from male donors only and PDK4 gene expression from female donors only. Testosterone or 17 β-estradiol treatment enhanced insulin-stimulated glucose incorporation into glycogen and AKT phosphorylation only in myotubes from female donors. Acute supra-physiological doses of testosterone or 17 β-estradiol reduced glucose metabolism, independent of sex origin of the cells. Moreover, acute testosterone treatment increased basal palmitate oxidation and disrupted the insulin-suppressive effect on palmitate oxidation. Increased glucocorticoid action leads to reduced whole body insulin action and may predispose to type 2 diabetes. Local conversion of cortisone to active cortisol by the enzyme 11β-hydroxysteroid dehydrogenase in target tissues may regulate tissue-specific roles of glucocorticoids in patho-physiological states. Chronic high dose exposure to cortisol or cortisone reduced glucose metabolism, and enhanced palmitate oxidation, via induction of PDK4 expression in myotubes. siRNA-mediated reduction or pharmacological inhibition of HSD1 prevented the effects of cortisone, but not cortisol, on metabolic responses. In conclusion, steroid hormones exert diverse effects in a dose and time dependent manner. Modulation of steroid hormone actions at specific regulatory steps may provide potential therapeutic entry points for metabolic disease and Type 2 diabetes. Moreover, attention should be focused on understanding sex-dependent differences in metabolic disease, and sex-origin of cells is important to consider when assessing hormonal responses in culture.
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