Review
KeynoteInhibition of 11ß-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target
Keynote
Section snippets
Glucocorticoids, obesity and metabolic disease
Glucocorticoids are well-known ubiquitous hormones playing a key role in modulating immune and inflammatory responses, regulating energy metabolism and cardiovascular homeostasis and the body's responses to stress. Opposing the action of insulin, glucocorticoids stimulate production of glucose, switching the homeostatic balance towards catabolism. Thus, glucocorticoids promote gluconeogenesis but inhibit beta-cell insulin secretion and peripheral glucose uptake 5, 6. They also increase protein
11ß-hydroxysteroid dehydrogenases (11ß-HSDs)
Two isoforms of 11ß-HSD are known, the products of distinct genes [7]. 11ß-HSD2, a high-affinity NAD-dependent dehydrogenase, is expressed mainly in mineralocorticoid target tissues (kidney, colon, salivary glands) [11]. This distribution reflects its role in protecting intrinsically non-selective MR from activation by cortisol and corticosterone, and thereby enabling selective aldosterone binding [12]. Additionally, 11ß-HSD2 is highly expressed in the placenta and the developing fetus,
11ß-HSD1 in obesity and the metabolic syndrome
To test the hypothesis that tissue-specific regulation of 11ß-HSD expression and activity contributes to obesity and its metabolic consequences, several animal studies have been performed. In leptin-resistant fatty Zucker rats, obesity associates with decreased 11ß-HSD1 activity and expression in the liver, but increased 11ß-HSD1 in the adipose tissue, notably in visceral fat [24]. Similar changes have been reported in leptin-deficient ob/ob mice [25]. It is noteworthy that basal 11ß-HSD1
Transgenic overexpression of 11ß-HSD1 models the metabolic syndrome
To dissect the pathogenic implications of elevated adipose 11ß-HSD1 in obesity, transgenic mice with 2–3-fold overexpression of 11ß-HSD1 in fat were generated, exploiting the adipocyte fatty acid binding protein (aP2) promoter [69] (Table 2). These aP2-HSD1 transgenic mice have elevated corticosterone levels in adipose tissue but unaltered plasma concentrations. The mice develop many features of the metabolic syndrome: glucose intolerance and insulin resistance (exacerbated further by high-fat
How is 11ß-HSD1 regulated?
Expression of 11ß-HSD1 is regulated by many factors including glucocorticoids, insulin, growth hormone, thyroid and sex hormones, cytokines, PPARα, PPARγ and perhaps other nuclear receptors (Figure 2). In vivo, in rat liver and hippocampus, glucocorticoids have been reported to regulate temporally 11ß-HSD1 expression and activity [14]. In human skeletal muscle, 11ß-HSD1 expression is upregulated by physiological concentrations of cortisol in a dose-dependent manner [47]. 11ß-HSD1 expression and
The role of 11ß-HSD1 in resolution of inflammation
The anti-inflammatory properties of glucocorticoids are well known, and these steroids are commonly used in clinical treatment of inflammatory disorders. Notwithstanding this, it has been suggested that although glucocorticoids have immunosuppressive effects in pharmacological doses, at physiological levels they provide a more immunomodulatory influence [6]. Chronic inflammation in such conditions as rheumatoid arthritis and asthma is believed to result from disturbance of the equilibrium
Inhibition of 11ß-HSD1 as a therapeutic target
It has been hypothesised that decreasing glucocorticoid activity in adipose tissue and liver might protect against the detrimental metabolic consequences of obesity. Two principal therapeutic strategies to diminish the exaggerated activation of a receptor may be identified: antagonism of the receptor and/or its signalling pathway or reducing ligand availability, either systemically or locally. Administration of GR antagonist RU38486 in Cushing's syndrome patients and in db/db mice decreases
Isozyme selectivity
Animal models described above, and experiments using 11ß-HSD1 inhibitors, have highlighted effects upon hepatic gluconeogenesis 75, 120, regulation of adipocyte differentiation, lipid metabolism 69, 153, lipoprotein profiles [77], insulin secretion and sensitivity [43], and blood pressure [70]. Several natural product derivatives, including carbenoxolone, glycyrrhetinic acid, metyrapone and ketoconazole have been shown to exhibit inhibitory activity against 11ß-HSD. However, none is fully
Conclusion
Here we present a review of animal and human studies on 11ß-HSD1 and give a rationale for the development of a new class of drugs by the pharmaceutical industry. The broad range of reported functions of 11ß-HSD1 point to the possibility that its inhibition would be successful in the treatment, prevention and prophylaxis of a range of medical disorders in which a decreased intracellular concentration of active glucocorticoids is desirable. Inevitably, for any potent therapy, there will be
Acknowledgements
We thank our colleagues in the Endocrinology Unit and particularly Dr Nicholas Morton for stimulating discussions. Work on 11ß-HSD1 in our laboratory is funded by a Wellcome Trust Programme Grant and awards from the Wellcome Trust, British Heart Foundation, Medical Research Council, European Union and Medical Research Scotland.
MALGORZATA WAMIL studied Medicine at the Medical University in Warsaw (Poland) and at the Free University of Berlin (Germany). Having received her degree in 2004, she followed a career in research as the British Heart Foundation PhD Fellow in Cardiovascular Science at the University of Edinburgh. Her research interests focus on identifying the key pathways downstream of 11ß-HSD1 in fat tissue using micro-array technology and bio-informatics analysis. In addition, she is working on the role of
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MALGORZATA WAMIL studied Medicine at the Medical University in Warsaw (Poland) and at the Free University of Berlin (Germany). Having received her degree in 2004, she followed a career in research as the British Heart Foundation PhD Fellow in Cardiovascular Science at the University of Edinburgh. Her research interests focus on identifying the key pathways downstream of 11ß-HSD1 in fat tissue using micro-array technology and bio-informatics analysis. In addition, she is working on the role of 11ß-HSD1 in oxysterol metabolism in adipocytes. Her long-term passion is to uncover the molecular mechanisms underpinning obesity-induced metabolic syndrome.
JONATHAN R. SECKL Jonathan Seckl is both medically and scientifically trained (MBBS at UCL, PhD in neuroendocrinology at ICL). A clinical endocrinologist and former Wellcome Trust Senior Clinical Research Fellow, Seckl's research focuses on glucocorticoid biology from ‘cloning to clinic’. The laboratory exploits technologies from molecular and cell biology through models in vivo to detailed clinical investigation. His main themes are the discovery and understanding of the importance of local tissue regeneration of glucocorticoids as a cause of and therapeutic target for age-related memory impairments and the metabolic syndrome-diabetes-obesity continuum. He also studies fetal ‘programming’ by glucocorticoids and the mechanism by which this leads to subsequent disorders in adult life. He has authored over 200 peer-reviewed scientific papers.