11beta-hydroxysteroid dehydrogenase type 1 and obesity.
The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing's syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects - despite the opposing plasma glucocorticoid profiles of Cushing's and idiopathic metabolic syndrome - remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11beta -hydroxysteroid dehydrogenase type 1 (11beta -HSD1). In order to determine whether elevated tissue 11beta -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11beta -HSD1 in adipose tissue or liver were made. Adipose-selective 11beta -HSD1 transgenic mice exhibited elevated intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11beta -HSD1 in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hypertension and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective 11beta -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment of the metabolic syndrome. Further, a transgenic model of therapeutic 11beta -HSD1 inhibition, 11beta -HSD1 gene knock-out (11beta -HSD1-/-) mice, exhibited improved glucose tolerance, a 'cardioprotective' lipid profile, reduced weight gain and visceral fat accumulation with chronic high-fat feeding. Recent evidence further suggests that high fat-mediated downregulation of adipose 11beta -HSD1 may be an endogenous pathway that underpins adaptive disease resistance in genetically predisposed mouse strains. This mechanism could feasibly make up a genetic component of innate obesity resistance in humans. The efficacy of 11beta -HSD1 inhibitors has recently been extended to include increased energy expenditure and reduction of arteriosclerosis, and therefore may be of significant therapeutic value in the metabolic syndrome, with complementary effects upon liver adipose tissue, muscle, pancreas and plaque-prone vessels.
Morton
Nicholas M
NM
Endocrinology Unit, Centre for Cardiovascular Sciences, Queens Medical Research Institute, Edinburgh University, Edinburgh, UK.
Seckl
Jonathan R
JR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000503:physiopathology; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology*; D010913:Pituitary-Adrenal System / Q000503:physiopathology
D001057:Apolipoproteins E; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone; D006854:Hydrocortisone