Review 11b-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome Amit Joharapurkar 1 , Nirav Dhanesha 1 , Gaurang Shah 2 , Rajendra Kharul 3 , Mukul Jain 1 Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India K. B. Institute of Pharmaceutical Education and Research, Gandhinagar 382023, India Advinus Therapeutics Ltd. Quantum Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase – I , Hinjewadi, Pune – 411057, India Correspondence: Amit Joharapurkar, e-mail: amitjoharapurkar@zyduscadila.com Abstract: Obesity and associated metabolic syndrome is one of the greatest health threat to the modern society. Cortisol excess and the gluco- corticoid receptor signaling pathway in the metabolically active tissues have been implicated in the development of diabetes and obesity. The key enzyme in the regeneration of intracellular cortisol is 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). 11b-HSD1 increases local cortisol production in metabolically active tissue types such as adipose and liver. Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. Clini- cal and preclinical studies indicate that 11b-HSD1 inhibitors are likely to exert major pharmacological actions in metabolically ac- tive tissues. These effects suggest that inhibition of 11b-HSD1 in vivo may be a novel therapeutic target for obesity, diabetes, and metabolic syndrome.The advancement of numerous structural classes of selective 11b-HSD1 inhibitors further indicates that more refined design and screening for isoform and tissue selectivity would yield potential therapeutics in this area. Key words: 11b-hydroxysteroid dehydrogenase type 1, metabolic syndrome, obesity, diabetes, glucocorticoids, liver, adipose Abbreviations: 11b-HSD – 11b-hydroxysteroid dehydroge- nase, ACTH – adrenocorticotropic hormone, DIO – diet induced obesity, G6Pase – glucose 6-phosphatase, GR – glucocorticoid receptor, HGO – hepatic glucose output, MR – mineralocorti- coid receptor, PEPCK – phosphoenol pyruvate carboxykinase Introduction Obesity is one of the most important contributors to ill health in the current century [26]. Central obesity, which is intra-abdominal fat accumulation, signifi- cantly increases the risk of mortality as well as comorbidities such as dyslipidemia, hypertension, type 2 diabetes mellitus, arthritic conditions and can- cer. Obesity is closely associated with insulin resis- tance, which eventually results in hyperinsulinemia. A chronic hyperinsulinemic state causes excessive in- sulin action in kidney, arterial walls, and sympathetic nervous system, resulting in elevated risk of increased blood pressure [27]. The metabolic syndrome (or syn- drome X) is a collection of these associated disorders. Prevalence of metabolic syndrome is largely in- 1055