Endocrine Abstracts

The Metabolic Syndrome (insulin resistance, hyperglycaemia, dyslipidaemia, hypertension) amplified by visceral obesity resembles Cushing's but plasma cortisol levels are not usually elevated. To explain this paradox altered tissue sensitivity to glucocorticoids has been invoked. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) reactivates cortisone to cortisol, thus amplifying local glucocorticoid action. An adipose-selective increase in 11b-HSD1 may underlie the Metabolic Syndrome. In both obese humans and rodents we found ~2-fold increased 11β-HSD1 activity and mRNA in abdominal adipose but not liver. To address causation, transgenic mice with ~2-fold overexpression of 11β-HSD1 selectively in adipose tissue were made. The mice have elevated intra-adipose and portal, but not systemic corticosterone levels and show visceral obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, overexpressing 11β-HSD1 in liver alone yields an attenuated Metabolic Syndrome with insulin resistance, dyslipidaemia, hypertension and fatty liver, but no obesity or glucose intolerance. To explore the therapeutic potential we made 11β-HSD1 knock-out mice on obesity-prone (C57BL/6J) and -resistant (MF-1) backgrounds. Both 11b-HSD1-/- strains have improved glucose tolerance and a 'cardioprotective' lipid profile, consistent with the insulin sensitization seen with non-selective inhibitors of 11β-HSD in healthy humans and patients with type 2 diabetes. C57BL/6J 11b-HSD1-/- mice had lower weight gain despite transient hyperphagia. 11b-HSD1-/- mice have reduced visceral fat accumulation with chronic high fat (HF) feeding, redistributing fat to 'metabolically favorable' peripheral depots. Isolated 11b-HSD1-/- adipocytes have higher basal and insulin-stimulated glucose uptake. Intriguingly, wild type mice down-regulated 11b-HSD1 in fat in response to HF diet. Moreover, metabolic disease-resistant A/J mice had both lower basal levels and down-regulated adipose 11b-HSD1 more markedly than metabolic disease-prone C57BL/6J mice. This suggests that down-regulation of adipose 11b-HSD1 represents an adaptive mechanism, more pronounced in metabolic disease-resistance, that counteracts the adverse metabolic consequences of chronic HF diet. 11β-HSD1 inhibitors may be of therapeutic value in the Metabolic Syndrome, with complementary effects upon liver and adipose tissue metabolism.