11-dehydrocorticosterone and Metabolic-Syndrome

Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which has led to investigation of the link between excess glucocorticoids and metabolic syndrome. Indeed, increased glucocorticoids from intracellular regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesized that increasing the substrate for 11β-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal axis. This elevated 11β-HSD1-derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprisingly liver-specific 11β-HSD1 knockout (LKO) mice given 11-DHC did not show any of the adverse metabolic effects seen in wild-type mice. This occurred despite the 11-DHC administration resulting in elevated circulating corticosterone, presumably from adipose tissue. Mice with global deletion of 11β-HSD1 (global knockout) were unaffected by treatment with 11-DHC, having no increase in circulating corticosterone and exhibiting no signs of metabolic impairment. Taken together, these data show that in the absence of 11β-HSD1 in the liver, mice are protected from the metabolic effects of 11-DHC administration, even though circulating glucocorticoids are increased. This implies that liver-derived intratissue glucocorticoids, rather than circulating glucocorticoids, contribute significantly to the development of metabolic syndrome and suggest that local action within hepatic tissue mediates these effects.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiposity; Animals; Biomarkers; Corticosterone; Down-Regulation; Glucocorticoids; Hyperinsulinism; Hyperphagia; Hypothalamo-Hypophyseal System; Insulin Resistance; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Pituitary-Adrenal System; Weight Gain

11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a microsomal NADPH-dependent oxidoreductase which elevates intracellular concentrations of active glucocorticoids. Data obtained from mouse strains with genetically manipulated 11HSD1 showed that local metabolism of glucocorticoids plays an important role in the development of metabolic syndrome. Tissue specific dysregulation of 11HSD1 was also found in other models of metabolic syndrome as well as in a number of clinical studies. Here, we studied local glucocorticoid action in the liver, subcutaneous adipose tissue (SAT) and skeletal muscles of male and female Prague hereditary hypertriglyceridemic rats (HHTg) and their normotriglyceridemic counterpart, the Wistar rats. 11HSD1 bioactivity was measured as a conversion of [(3)H]11-dehydrocorticosterone to [(3)H]corticosterone or vice versa. Additionally to express level of active 11HSD1 protein, enzyme activity was measured in tissue homogenates. mRNA abundance of 11HSD1, hexoso-6-phosphate dehydrogenase (H6PDH) and the glucocorticoid receptor (GR) was measured by real-time PCR. In comparison with normotriglyceridemic animals, female HHTg rats showed enhanced regeneration of glucocorticoids in the liver and the absence of any changes in SAT and skeletal muscle. In contrast to females, the glucocorticoid regeneration in males of HHTg rats was unchanged in liver, but stimulated in SAT and downregulated in muscle. Furthermore, SAT and skeletal muscle exhibited not only 11-reductase but also 11-oxidase catalyzed by 11HSD1. In females of both strains, 11-oxidase activity largely exceeded 11-reductase activity. No dramatic changes were found in the mRNA expression of H6PDH and GR. Our data provide evidence that the relationship between hypertriglyceridemia and glucocorticoid action is complex and gender specific.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Carbohydrate Dehydrogenases; Corticosterone; Disease Models, Animal; Female; Glucocorticoids; Hypertriglyceridemia; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Rats; Rats, Wistar; Receptors, Glucocorticoid; Sex Factors; Subcutaneous Fat