The role of steroid hormones in skeletal muscle metabolism
Author: Salehzadeh, Firoozeh
Date: 2011-06-14
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna.
Time: 09.00
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
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.
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.
List of papers:
I. Rune A, Salehzadeh F, Szekeres F, Kuhn I, Osler ME, and Al-Khalili L. (2009). Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women. Acta Physiol. (197), 207-15.
Fulltext (DOI)
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II. Salehzadeh F, Rune A, Osler M, Al-Khalili L. (2011). Testosterone or 17 β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. [Submitted]
III. Salehzadeh F, Guimaraes D, Al-Khalili L. (2011). Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro. [Manuscript]
IV. Salehzadeh F, Al-Khalili L, Kulkarni SS, Wang M, Lönnqvist F, Krook A. (2009). Glucocorticoid-mediated effects on metabolism are reversed by targeting 11 beta hydroxysteroid dehydrogenase type 1 in human skeletal muscle. Diabetes Metab Res Rev. (2009), 250–8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Rune A, Salehzadeh F, Szekeres F, Kuhn I, Osler ME, and Al-Khalili L. (2009). Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women. Acta Physiol. (197), 207-15.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Salehzadeh F, Rune A, Osler M, Al-Khalili L. (2011). Testosterone or 17 β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. [Submitted]
III. Salehzadeh F, Guimaraes D, Al-Khalili L. (2011). Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro. [Manuscript]
IV. Salehzadeh F, Al-Khalili L, Kulkarni SS, Wang M, Lönnqvist F, Krook A. (2009). Glucocorticoid-mediated effects on metabolism are reversed by targeting 11 beta hydroxysteroid dehydrogenase type 1 in human skeletal muscle. Diabetes Metab Res Rev. (2009), 250–8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Issue date: 2011-05-23
Rights:
Publication year: 2011
ISBN: 978-91-7457-377-0
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