Abstract
Obesity is closely associated with the metabolic syndrome including diabetes, dyslipidemia and hypertension. The best predictor of these morbidities is not total body fat mass but quantity of visceral fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution, and its action on target tissue depends not only on circulating levels but also on intracellular concentrations. Locally-enhanced action of glucocorticoid in adipose tissue has been implicated in the molecular basis of the metabolic syndrome. Evidence has accumulated that enzyme activity of 11β-hydroxysteoid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids from inactive forms within cells, and plays a central role in regulating intracellular glucocorticoid concentrations, is commonly elevated in fat depots from obese individuals. This suggests a role for adipose glucocorticoid (adiposteroid) in obesity and the metabolic syndrome. We have demonstrated that 11β-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. We also have revealed that adipose-specific 11β-HSD1 transgenic mice, which show increased enzyme activity to a similar extent seen in obese humans, develop distinguished visceral obesity with insulin resistance, dyslipidemia and hypertension. Recent reports have shown that selective inhibitors of the enzyme can ameliorate diabetes in genetically-diabetic obese mice. These data highlight the importance of adiposteriod activation in the pathophysiology of the metabolic syndrome. [Jpn J Physiol 54 Suppl:S8 (2004)]
