11β-Hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

Abstract 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing’s syndrome. Transgenic mice over-expressing 11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected from these metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has been achieved in liver with carbenoxolone, which enhances hepatic insulin sensitivity. Newer selective 11HSD1 inhibitors are in development, which may achieve reduced cortisol action in adipose tissue and confer therapeutic benefit in obese patients.