REVIEWS Drug Discovery Today  Volume 12, Numbers 13/14  July 2007 The metabolic syndrome phenotypically resembles Cushing’s, but plasma cortisol levels are normal. Intracellular cortisol regeneration by 11ß-hydroxysteroid dehydrogenase type 1 in adipose tissue might explain this paradox, but is this a realistic therapeutic target? Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target Malgorzata Wamil and Jonathan R. Seckl Endocrinology Unit, Centre for Cardiovascular Science, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11ß-HSD1 in adipose tissue. Transgenic mice overexpressing 11ß-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11ß-HSD1 knockout mice have a ‘cardioprotective’ phenotype, whose effects are also seen with 11ß-HSD1 inhibitors in rodents. However, any major metabolic effects of 11ß-HSD1 inhibition in humans are, as yet, unreported. 11ß-HSD1 null mice also resist congitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11ß-HSD1 inhibition is an emerging pleiotropic therapeutic target. The prevalence of obesity and its metabolic complications has been increasing rapidly over the past two decades [1]. Obesity is associated with an increased risk of type 2 diabetes, metabolic syndrome, cardiovascular disease, stroke and certain cancers. The World Health Organisation has estimated that worldwide 1.6 billion adults are overweight with at least 400 million of them clinically obese [2]. These gloomy raw statistics include increasing numbers of children and adolescents, foreshadowing a worsening trend in the future. Given that medical science has always risen to epidemic challenges, the paralleled increase in our understanding of metabolic pathways underlying obesity and its metabolic consequences is not surprising. Whether or not obesity in the absence of its complicating disorders increases mortality remains contentious [3]. What is clear is that obesity is major risk factor for several disorders that are themselves associated with high morbidity and mortality. These include type 2 diabetes, dyslipidaemia, hypertension and cardiovascular disease (which, together with visceral/abdominal obesity, comprise the metabolic syndrome), as well as several cancers, respiratory disorders, gallstones, osteoarthritis, depression and anxiety. Whilst prevention of these complications of obesity is a major impetus for research into prevention and treatment, another important if more contentious driving force of the extensive research in the field of obesity is the growing public expectation of a pharma- ceutical antidote to our ‘obesogenic environment’. Many novel druggable molecular targets have recently been identified. Several have entered drug development and even clinical practice, Reviews  KEYNOTE REVIEW 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 glu- cocorticoids as a cause of and therapeutic target for age-related memory impairments and the metabolic syndrome-diabetes-obesity continuum. He also stu- dies fetal ‘programming’ by glucocorticoids and the mechanism by which this leads to subsequent disor- ders in adult life. He has authored over 200 peer- reviewed scientific papers. Corresponding author: Seckl, J.R. (j.seckl@ed.ac.uk) 504 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2007.06.001