Endocrine Abstracts

Tissue-level regeneration of active glucocorticoids (GC) by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) now represents a promising therapeutic target for the treatment of metabolic syndrome. Proof of principle came largely from our transgenic animal models of altered tissue GC action, which delineated 11β-HSD1 as a major determinant of intracellular GC exposure and a molecular link between ‘Cushingoid’ and idiopathic obesity. Key among these observations was the visceral obesity, type 2 diabetes and hypertension caused by adipose tissue overexpression of 11β-HSD1 which provided the first ‘causal’ link between high adipose 11β-HSD1 and a metabolic syndrome. Liver overexpression of 11β-HSD1 produced mild insulin resistance, dyslipidaemia and hypertension without obesity. In contrast, mice with a ‘global’ knockout of 11β-HSD1 resisted visceral obesity and dyslipidaemia whilst exhibiting a protective adipose tissue adipokine profile and increased energy expenditure. Ectopic expression of the GC-inactivating 11β-HSD2 enzyme in adipose produced a protective phenotype similar to 11β-HSD1 knockout mice. More recently, we discovered that dietary fat potently down-regulates adipose 11β-HSD1 in rodents. Moreover, mouse strains that resist diet-induced obesity have low adipose 11β-HSD1 and can ‘switch-off’ the enzyme more readily than obesity-susceptible mice. Our new data show that diets enriched with saturated fats increase adipose 11β-HSD1 whereas unsaturated fats decrease it, suggesting a mechanism whereby the high saturated fat content of ‘Western’-style diets may exacerbate metabolic disease. Current studies also suggest 11β-HSD1 deficiency is associated with reduced accumulation of adipose tissue macrophages (that contribute to pathogenic inflammation in obesity), reduced preadipocyte differentiation and improvement of the insulin secretory capacity of pancreatic beta cells (where GC may trigger diabetes). Transgene-mediated overexpression in some of the key tissues has been initiated to further investigate the molecular mechanisms involved.

In summary, our transgenic and dietary intervention studies have been instrumental in describing the crucial endocrine role and novel functions of the intracellular enzyme 11β-HSD1 in the pathophysiology of metabolic syndrome and have laid the ground work for the major ongoing therapeutic drive to target this pathway in human disease.