- Email: [email protected]
Glucocorticoids, bone and energy metabolism
Glucocorticoids, bone and energy metabolism Mark S. Cooper, Markus J. Seibel, Hong Zhou PII: DOI: Reference:
S8756-3282(15)00219-7 doi: 10.1016/j.bone.2015.05.038 BON 10755
To appear in:
Bone
Received date: Revised date: Accepted date:
25 January 2015 25 May 2015 27 May 2015
Please cite this article as: Cooper Mark S., Seibel Markus J., Zhou Hong, Glucocorticoids, bone and energy metabolism, Bone (2015), doi: 10.1016/j.bone.2015.05.038
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Glucocorticoids, bone and energy metabolism
Glucocorticoids, bone and energy metabolism
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Mark S Cooper1, Markus J Seibel2, Hong Zhou2 1
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Adrenal Steroid Group, ANZAC Research Institute, Concord Repatriation General Hospital, Hospital Road, Concord Hospital, NSW, Australia, 2139.
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2
Bone Research Program, ANZAC Research Institute, Concord Repatriation General Hospital, Hospital Road, Concord Hospital, NSW, Australia, 2139.
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Address for correspondence:
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Prof Mark S Cooper, Adrenal Steroid Group, ANZAC Research Institute,
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Concord Repatriation General Hospital,
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Hospital Road,
NSW, 2139 Australia
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Concord Hospital,
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Phone: +61 2 97676775 Fax: +61 2 97677603
Email: [email protected]
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Glucocorticoids, bone and energy metabolism
Abstract: Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated
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with serious clinical features including altered body composition and the development of insulin
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resistance, impaired glucose tolerance an diabetes. It had been assumed that these adverse effects
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were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of
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glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and
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systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes
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induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone
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osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are
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Keywords:
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mediated through bone.
Glucocorticoids, diabetes, glucose tolerance, obesity, osteoblasts, osteocalcin
Highlights: 1. Prolonged circulating glucocorticoid excess has significant adverse effects on body composition and systemic fuel metabolism. 2. The action of glucocorticoids on body composition and systemic fuel metabolism is, at least in part, mediated through the osteoblast. 3. Osteocalcin is the bone derived substance most likely to link glucocorticoid action in osteoblasts to changes in body composition and systemic fuel metabolism.
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Glucocorticoids, bone and energy metabolism
Introduction: The prolonged use of therapeutic glucocorticoids is associated with a range of adverse effects (figure
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1). The detrimental effects on bone have received the greatest focus and there are now a range of
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therapeutic strategies available to reduce the negative effects of glucocorticoids on bone [1].
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Endogenous or exogenous glucocorticoid excess is also associated with other serious clinical features such as the development of insulin resistance, impaired glucose tolerance and frank diabetes [2].
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Glucocorticoids also cause changes in fat distribution favouring accumulation of central (visceral) fat at the expense of subcutaneous adipose tissue. Traditionally it has been thought that these adverse
MA
effects were mediated by direct effects of glucocorticoids on adipose tissue or the liver. Recent studies have questioned the role of these tissues in the abnormal energy metabolism associated
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with glucocorticoid excess [3-5]. At the same time other studies have indicated that these effects
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are, at least in part, mediated through the actions of glucocorticoids on bone [6].
Actions of glucocorticoids on energy metabolism
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Long term glucocorticoid treatment of humans or experimental animals leads to an increase in insulin resistance manifested as a reduced ability of insulin to suppress endogenous glucose production (reviewed in [7]). Short term treatment with glucocorticoids is associated with impaired release of insulin from the pancreas but this action is not prominent during long term glucocorticoid use [3, 8-10]. In clinical studies, patients with rheumatoid arthritis chronically treated with prednisolone tend to develop insulin resistance [8]. For most individuals blood glucose levels remain in the non-diabetic range but this is only achieved through a rise in plasma insulin levels. However, a significant proportion of glucocorticoid-treated individuals will develop glucose intolerance or diabetes mellitus. These patients tend to be those that already have a degree of insulin resistance due to their age, genetic or ethnic background, or other co-morbidities [11]. Many patients exposed
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to high doses of therapeutic glucocorticoids for prolonged periods develop also changes in the distribution of fat but there is a great variation in the degree to which this occurs between
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individuals. The basis for the changes in fat redistribution is unclear but differences in the response
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to glucocorticoids of subcutaneous and visceral adipose tissue have been proposed [2].
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Molecular actions of glucocorticoids
The action of glucocorticoids in a particular tissue is regulated by both receptor and ‘pre-receptor’
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mechanisms. As steroid hormones, glucocorticoids are able to pass across cell membranes. They are thought to primarily exert their effects by binding to specific intracellular receptors (glucocorticoid
D
receptors). The ability of glucocorticoids to bind to their receptors is regulated by intracellular
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enzymes that can convert glucocorticoids between active and inactive forms. The best characterised of these pre-receptor enzymes are the two types of 11-hydroxysteroid dehydrogenases (11-HSD)
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[12]. The type 1 enzyme (11-HSD1) is able to convert the inactive glucocorticoid cortisone (and its rodent equivalent dehydrocorticosterone) to the active glucocorticoid cortisol (corticosterone in
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rodents). By contrast, the type 2 enzyme (11-HSD2) inactivates cortisol and corticosterone to cortisone and dehydrocorticosterone, respectively (figure 2). 11-HSD1 is expressed in almost all tissues implicated in the effects of glucocorticoids on energy metabolism, including adipose, liver, muscle, pancreas and osteoblasts [13]. By contrast, 11-HSD2 expression is primarily restricted to cells involved in sodium homeostasis (kidney, colon, sweat and salivary glands). Human studies have indicated that the sensitivity of individuals to the adverse effects of glucocorticoids on bone, body composition and energy balance is, at least in part, linked to the activity of the 11b-HSD1 enzyme [14, 15]. The level of 11-HSD1 activity in healthy individuals predicted the response of bone markers such as osteocalcin and PINP to prednisolone treatment [14]. The changes in body composition seen in Cushing’s disease (hypercortisolism due to an ACTH secreting pituitary
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adenoma) have also been linked to the activity of this enzyme with low activity associated with relative protection from the glucocorticoid excess [15]. Animal studies have also highlighted the
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importance of 11-HSD1 in mediating the effects of glucocorticoids on body composition and energy
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metabolism. Mice with transgenic global deletion of 11-HSD1 were protected against the adverse
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metabolic effects of oral corticosterone relative to wild type mice despite a similar level of corticosterone being present in the circulation [4]. In contrast to the phenotype of mice with global
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deletion of 11-HSD1, targeted deletion of 11-HSD1 in either adipose tissue or the liver failed to reproduce the protective phenotype. This indicates that the effects of glucocorticoid excess on
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energy metabolism are not mediated through direct effects on adipose or fat tissues. Glucocorticoids can signal through a variety of mechanisms after binding to the GR. These include
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binding as a dimer to classical glucocorticoid response elements within the DNA, binding as
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monomers to non-classical response elements within DNA, or binding as a monomer to proteins
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involved in pro-inflammatory signalling pathways such as NF-B and AP-1 (figure 2) [16]. Subtle differences between individuals in their sensitivity to glucocorticoids have been reported based on polymorphic variants of the GR gene [17]. Such differences could explain some of the differences
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between individuals in the sensitivity to therapeutic glucocorticoid treatment.
Role of adipose and liver tissue in glucocorticoid-related dysmetabolism Although in vitro studies have demonstrated direct effects of glucocorticoids on a range of cell types involved in energy balance there is much less and often controversial evidence regarding how glucocorticoids exert their adverse effects in vivo. The traditional assumption that adipose tissue in particular is the target of glucocorticoid action has been challenged by recent in vivo studies. Using tissue microdialysis and hyperinsulinemic euglycemic clamp studies the effect of overnight hydrocortisone (cortisol) infusions on subcutaneous adipose tissue insulin sensitivity was examined 5
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[3]. It was found that hydrocortisone treatment induced systemic insulin resistance but sensitised adipose tissue to the effects of insulin. Similar insulin sensitisation of adipocytes by glucocorticoids
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was seen in in vitro studies [3]. The authors felt that the induction of insulin resistance was most
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likely through direct or indirect effects of glucocorticoids on muscle rather than adipose tissue. In vivo studies utilising genetically modified mouse models provide the opportunity to determine whether effects of glucocorticoids on a particular tissue are mediated directly or indirectly. Mice
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with total deletion of 11-HSD1 are protected against the adverse metabolic effects of glucocorticoids. However, selective deletion of 11-HSD1 in either liver or adipose tissue fails to give
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any protection. This suggests that glucocorticoid excess induces systemic changes in energy
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metabolism through an alternative tissue or tissues.
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Role of bone tissue in glucocorticoid related dysmetabolism Lee and colleagues reported that in mice, the osteoblast-specific product, osteocalcin reduces insulin resistance and stimulates pancreatic beta cell proliferation and production of insulin [18] (see also
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article by Clemens and Karsenty in this issue). Osteocalcin is a non-collagenous protein which is unique in that it is synthesised and secreted exclusively by osteoblasts. The peptide undergoes posttranslational modification via -carboxylation of 3 glutamic acid residues, allowing it to bind to the mineralized bone matrix [19, 20]. A proportion of osteocalcin remains uncarboxylated so that both carboxylated and uncarboxylated osteocalcin are found in the circulation [21]. Mice lacking osteocalcin exhibit increased visceral obesity, higher blood glucose and lower serum insulin levels [22]. Further studies demonstrated that infusion of undercarboxylated osteocalcin reduced diet and chemically-induced weight-gain, fat mass, hepatic steatosis and insulin resistance in mice [23]. Osteocalcin thus appears to improve glucose uptake into muscle, adipose and the liver [22]. The finding that bone cells are intimately involved in the regulation of systemic energy metabolism in 6
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mice (and possibly humans) raised the possibility that bone could also be a mediator of the adverse effects of glucocorticoids on energy metabolism. This hypothesis was additionally plausible since the
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expression of osteocalcin by osteoblasts is exquisitely sensitive to the action of glucocorticoids [6,
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14]. Indeed, glucocorticoids are the most powerful inhibitor of osteocalcin expression and release
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known and the level of osteocalcin has been used as a clinical marker of glucocorticoid effects on the skeleton for several decades [14, 24].
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The role of bone in glucocorticoid related dysmetabolism has now been examined in experimental mice in which the action of glucocorticoids within osteoblasts/osteocytes has been abrogated. This
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blockage was achieved by the transgenic expression of the 11-HSD2 enzyme selectively under the control of the rat 2.3kb type 1 collagen promoter. This promoter has been shown to have expression
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restricted to mature osteoblasts and osteocytes [25]. The expression of 11-HSD2 in these cells
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would be expected to render them highly resistant to the effects of corticosterone and this has
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indeed been demonstrated in in vitro studies [26]. These mice were originally generated to examine the effects of glucocorticoids on bone metabolism but unexpectedly were found to be resistant to the metabolic effects of glucocorticoid excess [6]. Treatment with glucocorticoids over a 7 to 28 day
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period resulted in impaired glucose tolerance, reduced insulin sensitivity, increased adipose tissue mass and hepatic lipid accumulation in wild type littermate animals. By contrast the transgenic littermates expressing 11-HSD2 within osteoblasts/osteocytes had a greatly attenuated impact of glucocorticoids on these parameters). These results suggested that glucocorticoids regulate a factor secreted from bone which was able to influence energy metabolism. Based upon the reports by Karsenty’s group [22], osteocalcin was the leading candidate. Indeed, mice with transgenic expression of 11-HSD2 were found to have preservation of the level of osteocalcin in their serum whereas the level was significantly reduced within 24 hours in wild type mice treated with glucocorticoids [6]. To further clarify the role of osteocalcin in the protection against dysmetabolism in response to glucocorticoids, osteocalcin 7
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levels were restored in wild type mice in which osteocalcin was expressed heterotopically in the liver. This gene therapy was achieved through the use of hemodynamic tail vein injections to
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transfect hepatocytes in vivo with a plasmid containing osteocalcin and a control empty vector. The
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gene therapy was also designed to express a vector engineered to cause synthesis of a mutated
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osteocalcin protein which was incapable of being carboxylated. The expression of both of these forms of osteocalcin was examined since in other situations it had been observed that the hormonal
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effects of osteocalcin were primarily seen with the un- or under-carboxylated forms of osteocalcin rather than the carboxylated form [22]. Mice with heterotopic expression of osteocalcin had normal
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levels of osteocalcin under normal conditions but remain the normal osteocalcin levels in response to glucocorticoid treatment. In a manner similar to that seen in 11-HSD2 transgenic mice, the
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expression of osteocalcin protected mice against the development of glucose intolerance, insulin
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resistance and adipose tissue expansion when they were treated with glucocorticoids. Significantly, this protection was seen to a similar extent in the mice that expressed the wild type osteocalcin as
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the mice expressing the mutant (uncarboxylated) form of osteocalcin. This ability of both forms of osteocalcin to protect against the adverse metabolic effects of glucocorticoids is in contrast to
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studies examining the ability of osteocalcin to regulate glucose metabolism in the resting state where un- or under-carboxylated osteocalcin appears to be more important than carboxylated osteocalcin. A schematic overview of how glucocorticoids impact on energy metabolism through their effects on osteoblasts is illustrated in figure 3. Another difference in the relationship between osteocalcin and glucose metabolism in the glucocorticoid and non-glucocorticoid treated state appeared to be the role of pancreatic insulin release. In the non-glucocorticoid treated state osteocalcin has been reported to increase beta cell insulin production. In the glucocorticoid treated state insulin levels were increased in all mice regardless of genotype or level of osteocalcin expression. However, non-glucocorticoid treated mice receiving either osteocalcin or mutant osteocalcin vectors displayed fasting serum insulin levels that
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remained unchanged compared with both their own beseline and the levels seen in empty vector mice suggesting that osteocalcin replacement results in improved peripheral insulin sensitivity but
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not insulin production.
Clinical studies and clinical implications
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The above studies point towards bone, and specifically osteocalcin and/or related molecules, being significant regulators of energy metabolism in the context of glucocorticoid treatment. This has
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significant clinical implications since the metabolic adverse effects of glucocorticoids are difficult to counteract clinically. There is only a limited amount of clinical data relating to the relationship
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between glucocorticoids, osteocalcin and changes in energy metabolism. The situation is particularly
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complicated since most people treated with glucocorticoids will have an underlying disease that itself could influence systemic energy balance and glucose homeostasis [27]. This is compounded by
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the lack of availability of clinical approaches to selectively raise serum osteocalcin levels. One recent study has overcome some of these limitations by examining patients treated with bisphosphonates,
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teriparatide (PTH1-34) or calcium and vitamin D alone for glucocorticoid induced osteoporosis [28]. Teriparatide treatment is known to stimulate the level of osteocalcin whereas bisphosphonates reduce the level. This prospective, non-randomised study involved 111 patients 45 of which received bisphosphonates, 33 which received teriparatide and 33 who received calcium vitamin D alone. All subjects were followed up for 12 months and the changes in HbA1c and fasting plasma glucose were examined. It was found that there was no impact of bisphosphonate or calcium and vitamin D treatment alone on glycemic control over the 12 month period. However, in the teriparatide group there was a small but statistical significant improvement in HbA1c for the patients treated with teriparatide. This finding suggests that a treatment which stimulates osteocalcin has the potential to improve glycemic control in the setting of chronic glucocorticoid treatment. However, there are a
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number of caveats and limitations with the study including the lack of any change in fasting glucose in the patients treated with teriparatide. Additionally changes to diabetic medications were allowed
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through the study at the discretion of the patients’ physicians and this could have confounded the
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results. Currently this study remains the only clinical study examining the relationship between
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glucocorticoids, osteocalcin and body composition. Additional evidence regarding the clinical importance of osteocalcin in particular and the bone-energy metabolism link in general in the
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context of glucocorticoid excess may only come about when more specific ways of increasing
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osteocalcin levels or stimulating the action of osteocalcin within target tissues are developed.
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Conclusions
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In addition to there being a link between the skeleton and energy metabolism during normal physiology, there is now good evidence for an equivalent link mediating some of the adverse
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metabolic effects of glucocorticoid excess. Whilst the animal data suggests that this effect is relatively strong, clinical studies that fully address this potential mechanism in humans are lacking.
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Additionally, the detailed molecular mechanisms by which osteocalcin exerts its action, including the exact receptor(s) and tissues of action remain uncertain.
Acknowledgements: This work was supported by Project Grants from NHMRC to Hong Zhou and Markus Seibel (402462 and 632819) and from Arthritis Research UK to Mark Cooper (17730 and 18081).
References:
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Seibel, M.J., M.S. Cooper, and H. Zhou, Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol, 2013. 1(1): p. 59-70. Fernandez-Rodriguez, E., P.M. Stewart, and M.S. Cooper, The pituitary-adrenal axis and body composition. Pituitary, 2009. 12: p. 105-115. Hazlehurst, J.M., et al., Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue in vivo. J Clin Endocrinol Metab, 2013. 98(4): p. 1631-40. Morgan, S.A., et al., 11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A, 2014. 111(24): p. E2482-91. Lavery, G.G., et al., Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology, 2012. 153(7): p. 3236-3248. Brennan-Speranza, T.C., et al., Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J.Clin.Invest, 2012. 122(11): p. 4172-4189. Rafacho, A., et al., Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. J Endocrinol, 2014. 223(3): p. R4962. Petersons, C.J., et al., Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal adiposity in patients with inflammatory rheumatologic disease. Diabetes Care, 2013. 36(9): p. 2822-9. Nicod, N., et al., Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers. Obes Res, 2003. 11(5): p. 625-31. Beard, J.C., et al., Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men. Am J Physiol, 1984. 247(5 Pt 1): p. E592-6. van Raalte, D.H., D.M. Ouwens, and M. Diamant, Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest, 2009. 39(2): p. 81-93. Raza, K., R. Hardy, and M.S. Cooper, The 11beta-hydroxysteroid dehydrogenase enzymes-arbiters of the effects of glucocorticoids in synovium and bone. Rheumatology.(Oxford), 2010. 49(11): p. 2016-2023. Gathercole, L.L., et al., 11beta-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr.Rev., 2013. 34(4): p. 525-555. Cooper, M.S., et al., 11-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J.Clin.Endocrinol.Metab, 2003. 88(8): p. 3874-3877. Tomlinson, J.W., et al., Absence of Cushingoid Phenotype in a Patient with Cushing's Disease due to Defective Cortisone to Cortisol Conversion. J.Clin.Endocrinol.Metab, 2002. 87(1): p. 5762. Cooper, M.S., H. Zhou, and M.J. Seibel, Selective glucocorticoid receptor agonists: glucocorticoid therapy with no regrets? J Bone Miner Res, 2012. 27(11): p. 2238-41. Manenschijn, L., et al., Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann N.Y.Acad.Sci., 2009. 1179: p. 179-198. !!! INVALID CITATION !!! Calvo, M.S., D.R. Eyre, and C.M. Gundberg, Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev, 1996. 17(4): p. 333-68. Gundberg, C.M., Matrix proteins. Osteoporos Int, 2003. 14 Suppl 5: p. S37-40; discussion S40-2. Gundberg, C.M., et al., Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab, 1998. 83(9): p. 3258-66. Lee, N.K., et al., Endocrine regulation of energy metabolism by the skeleton. Cell, 2007. 130(3): p. 456-469.
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Ferron, M., et al., Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A, 2008. 105(13): p. 5266-70. Shane, E., et al., Bone loss and turnover after cardiac transplantation. J Clin Endocrinol Metab, 1997. 82(5): p. 1497-506. Dacic, S., et al., Col1a1-driven transgenic markers of osteoblast lineage progression. J.Bone Miner.Res, 2001. 16(7): p. 1228-1236. Woitge, H., et al., Cloning and in vitro characterization of alpha 1(I)-collagen 11 betahydroxysteroid dehydrogenase type 2 transgenes as models for osteoblast-selective inactivation of natural glucocorticoids. Endocrinology, 2001. 142(3): p. 1341-1348. den, U.D., et al., Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum, 2012. 64(3): p. 639-646. Mazziotti, G., et al., Outcome of glucose homeostasis in patients with glucocorticoid-induced osteoporosis undergoing treatment with bone active-drugs. Bone, 2014. 67: p. 175-80.
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Legend for figures: Figure 1: Illustration of the main therapeutic benefits and adverse effects of systemic
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glucocorticoid therapy.
Figure 2: Schematic overview of the action of glucocorticoids. Glucocorticoids are interconverted
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between inactive and active forms in the cytoplasm of target cells by the 11-hydroxysteroid dehydrogenase (11-HSD) enzymes. Active glucocorticoids when bound to glucocorticoid receptors
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(GR) can bind directly to glucocorticoid responsive elements to alter gene expression. Alternatively, glucocorticoid bound GR can interfere with the signalling of pro-inflammatory pathways such as
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nuclear factor kappa-B (NF-B) or activator protein 1 (AP-1 – formed from fos and jun factors).
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Figure 3: Schematic illustration of the role that bone, osteoblasts and osteocalcin have in mediating the changes in energy metabolism seen during glucocorticoid treatment.
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Glucocorticoids are likely to have direct effects on tissues such as liver, adipose tissue and muscle. However, they additionally can exert actions on these tissues through indirect effects resulting from suppression of secretion of osteocalcin by osteoblasts. These effects further lead to an increase in insulin secretion by the pancreas.
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S8756-3282(15)00219-7 doi: 10.1016/j.bone.2015.05.038 BON 10755
To appear in:
Bone
Received date: Revised date: Accepted date:
25 January 2015 25 May 2015 27 May 2015
Please cite this article as: Cooper Mark S., Seibel Markus J., Zhou Hong, Glucocorticoids, bone and energy metabolism, Bone (2015), doi: 10.1016/j.bone.2015.05.038
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Glucocorticoids, bone and energy metabolism
Glucocorticoids, bone and energy metabolism
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Mark S Cooper1, Markus J Seibel2, Hong Zhou2 1
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Adrenal Steroid Group, ANZAC Research Institute, Concord Repatriation General Hospital, Hospital Road, Concord Hospital, NSW, Australia, 2139.
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2
Bone Research Program, ANZAC Research Institute, Concord Repatriation General Hospital, Hospital Road, Concord Hospital, NSW, Australia, 2139.
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Address for correspondence:
MA
Prof Mark S Cooper, Adrenal Steroid Group, ANZAC Research Institute,
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Concord Repatriation General Hospital,
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Hospital Road,
NSW, 2139 Australia
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Concord Hospital,
AC
Phone: +61 2 97676775 Fax: +61 2 97677603
Email: [email protected]
1
ACCEPTED MANUSCRIPT
Glucocorticoids, bone and energy metabolism
Abstract: Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated
T
with serious clinical features including altered body composition and the development of insulin
IP
resistance, impaired glucose tolerance an diabetes. It had been assumed that these adverse effects
SC R
were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of
NU
glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and
MA
systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes
D
induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone
TE
osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are
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Keywords:
CE P
mediated through bone.
Glucocorticoids, diabetes, glucose tolerance, obesity, osteoblasts, osteocalcin
Highlights: 1. Prolonged circulating glucocorticoid excess has significant adverse effects on body composition and systemic fuel metabolism. 2. The action of glucocorticoids on body composition and systemic fuel metabolism is, at least in part, mediated through the osteoblast. 3. Osteocalcin is the bone derived substance most likely to link glucocorticoid action in osteoblasts to changes in body composition and systemic fuel metabolism.
2
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Glucocorticoids, bone and energy metabolism
Introduction: The prolonged use of therapeutic glucocorticoids is associated with a range of adverse effects (figure
T
1). The detrimental effects on bone have received the greatest focus and there are now a range of
IP
therapeutic strategies available to reduce the negative effects of glucocorticoids on bone [1].
SC R
Endogenous or exogenous glucocorticoid excess is also associated with other serious clinical features such as the development of insulin resistance, impaired glucose tolerance and frank diabetes [2].
NU
Glucocorticoids also cause changes in fat distribution favouring accumulation of central (visceral) fat at the expense of subcutaneous adipose tissue. Traditionally it has been thought that these adverse
MA
effects were mediated by direct effects of glucocorticoids on adipose tissue or the liver. Recent studies have questioned the role of these tissues in the abnormal energy metabolism associated
D
with glucocorticoid excess [3-5]. At the same time other studies have indicated that these effects
CE P
TE
are, at least in part, mediated through the actions of glucocorticoids on bone [6].
Actions of glucocorticoids on energy metabolism
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Long term glucocorticoid treatment of humans or experimental animals leads to an increase in insulin resistance manifested as a reduced ability of insulin to suppress endogenous glucose production (reviewed in [7]). Short term treatment with glucocorticoids is associated with impaired release of insulin from the pancreas but this action is not prominent during long term glucocorticoid use [3, 8-10]. In clinical studies, patients with rheumatoid arthritis chronically treated with prednisolone tend to develop insulin resistance [8]. For most individuals blood glucose levels remain in the non-diabetic range but this is only achieved through a rise in plasma insulin levels. However, a significant proportion of glucocorticoid-treated individuals will develop glucose intolerance or diabetes mellitus. These patients tend to be those that already have a degree of insulin resistance due to their age, genetic or ethnic background, or other co-morbidities [11]. Many patients exposed
3
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to high doses of therapeutic glucocorticoids for prolonged periods develop also changes in the distribution of fat but there is a great variation in the degree to which this occurs between
T
individuals. The basis for the changes in fat redistribution is unclear but differences in the response
SC R
IP
to glucocorticoids of subcutaneous and visceral adipose tissue have been proposed [2].
NU
Molecular actions of glucocorticoids
The action of glucocorticoids in a particular tissue is regulated by both receptor and ‘pre-receptor’
MA
mechanisms. As steroid hormones, glucocorticoids are able to pass across cell membranes. They are thought to primarily exert their effects by binding to specific intracellular receptors (glucocorticoid
D
receptors). The ability of glucocorticoids to bind to their receptors is regulated by intracellular
TE
enzymes that can convert glucocorticoids between active and inactive forms. The best characterised of these pre-receptor enzymes are the two types of 11-hydroxysteroid dehydrogenases (11-HSD)
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[12]. The type 1 enzyme (11-HSD1) is able to convert the inactive glucocorticoid cortisone (and its rodent equivalent dehydrocorticosterone) to the active glucocorticoid cortisol (corticosterone in
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rodents). By contrast, the type 2 enzyme (11-HSD2) inactivates cortisol and corticosterone to cortisone and dehydrocorticosterone, respectively (figure 2). 11-HSD1 is expressed in almost all tissues implicated in the effects of glucocorticoids on energy metabolism, including adipose, liver, muscle, pancreas and osteoblasts [13]. By contrast, 11-HSD2 expression is primarily restricted to cells involved in sodium homeostasis (kidney, colon, sweat and salivary glands). Human studies have indicated that the sensitivity of individuals to the adverse effects of glucocorticoids on bone, body composition and energy balance is, at least in part, linked to the activity of the 11b-HSD1 enzyme [14, 15]. The level of 11-HSD1 activity in healthy individuals predicted the response of bone markers such as osteocalcin and PINP to prednisolone treatment [14]. The changes in body composition seen in Cushing’s disease (hypercortisolism due to an ACTH secreting pituitary
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adenoma) have also been linked to the activity of this enzyme with low activity associated with relative protection from the glucocorticoid excess [15]. Animal studies have also highlighted the
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importance of 11-HSD1 in mediating the effects of glucocorticoids on body composition and energy
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metabolism. Mice with transgenic global deletion of 11-HSD1 were protected against the adverse
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metabolic effects of oral corticosterone relative to wild type mice despite a similar level of corticosterone being present in the circulation [4]. In contrast to the phenotype of mice with global
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deletion of 11-HSD1, targeted deletion of 11-HSD1 in either adipose tissue or the liver failed to reproduce the protective phenotype. This indicates that the effects of glucocorticoid excess on
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energy metabolism are not mediated through direct effects on adipose or fat tissues. Glucocorticoids can signal through a variety of mechanisms after binding to the GR. These include
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binding as a dimer to classical glucocorticoid response elements within the DNA, binding as
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monomers to non-classical response elements within DNA, or binding as a monomer to proteins
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involved in pro-inflammatory signalling pathways such as NF-B and AP-1 (figure 2) [16]. Subtle differences between individuals in their sensitivity to glucocorticoids have been reported based on polymorphic variants of the GR gene [17]. Such differences could explain some of the differences
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between individuals in the sensitivity to therapeutic glucocorticoid treatment.
Role of adipose and liver tissue in glucocorticoid-related dysmetabolism Although in vitro studies have demonstrated direct effects of glucocorticoids on a range of cell types involved in energy balance there is much less and often controversial evidence regarding how glucocorticoids exert their adverse effects in vivo. The traditional assumption that adipose tissue in particular is the target of glucocorticoid action has been challenged by recent in vivo studies. Using tissue microdialysis and hyperinsulinemic euglycemic clamp studies the effect of overnight hydrocortisone (cortisol) infusions on subcutaneous adipose tissue insulin sensitivity was examined 5
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[3]. It was found that hydrocortisone treatment induced systemic insulin resistance but sensitised adipose tissue to the effects of insulin. Similar insulin sensitisation of adipocytes by glucocorticoids
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was seen in in vitro studies [3]. The authors felt that the induction of insulin resistance was most
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likely through direct or indirect effects of glucocorticoids on muscle rather than adipose tissue. In vivo studies utilising genetically modified mouse models provide the opportunity to determine whether effects of glucocorticoids on a particular tissue are mediated directly or indirectly. Mice
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with total deletion of 11-HSD1 are protected against the adverse metabolic effects of glucocorticoids. However, selective deletion of 11-HSD1 in either liver or adipose tissue fails to give
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any protection. This suggests that glucocorticoid excess induces systemic changes in energy
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metabolism through an alternative tissue or tissues.
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Role of bone tissue in glucocorticoid related dysmetabolism Lee and colleagues reported that in mice, the osteoblast-specific product, osteocalcin reduces insulin resistance and stimulates pancreatic beta cell proliferation and production of insulin [18] (see also
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article by Clemens and Karsenty in this issue). Osteocalcin is a non-collagenous protein which is unique in that it is synthesised and secreted exclusively by osteoblasts. The peptide undergoes posttranslational modification via -carboxylation of 3 glutamic acid residues, allowing it to bind to the mineralized bone matrix [19, 20]. A proportion of osteocalcin remains uncarboxylated so that both carboxylated and uncarboxylated osteocalcin are found in the circulation [21]. Mice lacking osteocalcin exhibit increased visceral obesity, higher blood glucose and lower serum insulin levels [22]. Further studies demonstrated that infusion of undercarboxylated osteocalcin reduced diet and chemically-induced weight-gain, fat mass, hepatic steatosis and insulin resistance in mice [23]. Osteocalcin thus appears to improve glucose uptake into muscle, adipose and the liver [22]. The finding that bone cells are intimately involved in the regulation of systemic energy metabolism in 6
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mice (and possibly humans) raised the possibility that bone could also be a mediator of the adverse effects of glucocorticoids on energy metabolism. This hypothesis was additionally plausible since the
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expression of osteocalcin by osteoblasts is exquisitely sensitive to the action of glucocorticoids [6,
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14]. Indeed, glucocorticoids are the most powerful inhibitor of osteocalcin expression and release
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known and the level of osteocalcin has been used as a clinical marker of glucocorticoid effects on the skeleton for several decades [14, 24].
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The role of bone in glucocorticoid related dysmetabolism has now been examined in experimental mice in which the action of glucocorticoids within osteoblasts/osteocytes has been abrogated. This
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blockage was achieved by the transgenic expression of the 11-HSD2 enzyme selectively under the control of the rat 2.3kb type 1 collagen promoter. This promoter has been shown to have expression
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restricted to mature osteoblasts and osteocytes [25]. The expression of 11-HSD2 in these cells
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would be expected to render them highly resistant to the effects of corticosterone and this has
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indeed been demonstrated in in vitro studies [26]. These mice were originally generated to examine the effects of glucocorticoids on bone metabolism but unexpectedly were found to be resistant to the metabolic effects of glucocorticoid excess [6]. Treatment with glucocorticoids over a 7 to 28 day
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period resulted in impaired glucose tolerance, reduced insulin sensitivity, increased adipose tissue mass and hepatic lipid accumulation in wild type littermate animals. By contrast the transgenic littermates expressing 11-HSD2 within osteoblasts/osteocytes had a greatly attenuated impact of glucocorticoids on these parameters). These results suggested that glucocorticoids regulate a factor secreted from bone which was able to influence energy metabolism. Based upon the reports by Karsenty’s group [22], osteocalcin was the leading candidate. Indeed, mice with transgenic expression of 11-HSD2 were found to have preservation of the level of osteocalcin in their serum whereas the level was significantly reduced within 24 hours in wild type mice treated with glucocorticoids [6]. To further clarify the role of osteocalcin in the protection against dysmetabolism in response to glucocorticoids, osteocalcin 7
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levels were restored in wild type mice in which osteocalcin was expressed heterotopically in the liver. This gene therapy was achieved through the use of hemodynamic tail vein injections to
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transfect hepatocytes in vivo with a plasmid containing osteocalcin and a control empty vector. The
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gene therapy was also designed to express a vector engineered to cause synthesis of a mutated
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osteocalcin protein which was incapable of being carboxylated. The expression of both of these forms of osteocalcin was examined since in other situations it had been observed that the hormonal
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effects of osteocalcin were primarily seen with the un- or under-carboxylated forms of osteocalcin rather than the carboxylated form [22]. Mice with heterotopic expression of osteocalcin had normal
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levels of osteocalcin under normal conditions but remain the normal osteocalcin levels in response to glucocorticoid treatment. In a manner similar to that seen in 11-HSD2 transgenic mice, the
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expression of osteocalcin protected mice against the development of glucose intolerance, insulin
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resistance and adipose tissue expansion when they were treated with glucocorticoids. Significantly, this protection was seen to a similar extent in the mice that expressed the wild type osteocalcin as
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the mice expressing the mutant (uncarboxylated) form of osteocalcin. This ability of both forms of osteocalcin to protect against the adverse metabolic effects of glucocorticoids is in contrast to
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studies examining the ability of osteocalcin to regulate glucose metabolism in the resting state where un- or under-carboxylated osteocalcin appears to be more important than carboxylated osteocalcin. A schematic overview of how glucocorticoids impact on energy metabolism through their effects on osteoblasts is illustrated in figure 3. Another difference in the relationship between osteocalcin and glucose metabolism in the glucocorticoid and non-glucocorticoid treated state appeared to be the role of pancreatic insulin release. In the non-glucocorticoid treated state osteocalcin has been reported to increase beta cell insulin production. In the glucocorticoid treated state insulin levels were increased in all mice regardless of genotype or level of osteocalcin expression. However, non-glucocorticoid treated mice receiving either osteocalcin or mutant osteocalcin vectors displayed fasting serum insulin levels that
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remained unchanged compared with both their own beseline and the levels seen in empty vector mice suggesting that osteocalcin replacement results in improved peripheral insulin sensitivity but
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not insulin production.
Clinical studies and clinical implications
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The above studies point towards bone, and specifically osteocalcin and/or related molecules, being significant regulators of energy metabolism in the context of glucocorticoid treatment. This has
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significant clinical implications since the metabolic adverse effects of glucocorticoids are difficult to counteract clinically. There is only a limited amount of clinical data relating to the relationship
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between glucocorticoids, osteocalcin and changes in energy metabolism. The situation is particularly
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complicated since most people treated with glucocorticoids will have an underlying disease that itself could influence systemic energy balance and glucose homeostasis [27]. This is compounded by
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the lack of availability of clinical approaches to selectively raise serum osteocalcin levels. One recent study has overcome some of these limitations by examining patients treated with bisphosphonates,
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teriparatide (PTH1-34) or calcium and vitamin D alone for glucocorticoid induced osteoporosis [28]. Teriparatide treatment is known to stimulate the level of osteocalcin whereas bisphosphonates reduce the level. This prospective, non-randomised study involved 111 patients 45 of which received bisphosphonates, 33 which received teriparatide and 33 who received calcium vitamin D alone. All subjects were followed up for 12 months and the changes in HbA1c and fasting plasma glucose were examined. It was found that there was no impact of bisphosphonate or calcium and vitamin D treatment alone on glycemic control over the 12 month period. However, in the teriparatide group there was a small but statistical significant improvement in HbA1c for the patients treated with teriparatide. This finding suggests that a treatment which stimulates osteocalcin has the potential to improve glycemic control in the setting of chronic glucocorticoid treatment. However, there are a
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number of caveats and limitations with the study including the lack of any change in fasting glucose in the patients treated with teriparatide. Additionally changes to diabetic medications were allowed
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through the study at the discretion of the patients’ physicians and this could have confounded the
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results. Currently this study remains the only clinical study examining the relationship between
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glucocorticoids, osteocalcin and body composition. Additional evidence regarding the clinical importance of osteocalcin in particular and the bone-energy metabolism link in general in the
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context of glucocorticoid excess may only come about when more specific ways of increasing
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osteocalcin levels or stimulating the action of osteocalcin within target tissues are developed.
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Conclusions
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In addition to there being a link between the skeleton and energy metabolism during normal physiology, there is now good evidence for an equivalent link mediating some of the adverse
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metabolic effects of glucocorticoid excess. Whilst the animal data suggests that this effect is relatively strong, clinical studies that fully address this potential mechanism in humans are lacking.
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Additionally, the detailed molecular mechanisms by which osteocalcin exerts its action, including the exact receptor(s) and tissues of action remain uncertain.
Acknowledgements: This work was supported by Project Grants from NHMRC to Hong Zhou and Markus Seibel (402462 and 632819) and from Arthritis Research UK to Mark Cooper (17730 and 18081).
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Legend for figures: Figure 1: Illustration of the main therapeutic benefits and adverse effects of systemic
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glucocorticoid therapy.
Figure 2: Schematic overview of the action of glucocorticoids. Glucocorticoids are interconverted
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between inactive and active forms in the cytoplasm of target cells by the 11-hydroxysteroid dehydrogenase (11-HSD) enzymes. Active glucocorticoids when bound to glucocorticoid receptors
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(GR) can bind directly to glucocorticoid responsive elements to alter gene expression. Alternatively, glucocorticoid bound GR can interfere with the signalling of pro-inflammatory pathways such as
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nuclear factor kappa-B (NF-B) or activator protein 1 (AP-1 – formed from fos and jun factors).
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Figure 3: Schematic illustration of the role that bone, osteoblasts and osteocalcin have in mediating the changes in energy metabolism seen during glucocorticoid treatment.
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Glucocorticoids are likely to have direct effects on tissues such as liver, adipose tissue and muscle. However, they additionally can exert actions on these tissues through indirect effects resulting from suppression of secretion of osteocalcin by osteoblasts. These effects further lead to an increase in insulin secretion by the pancreas.
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