Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice

摘要

Glucocorticoids have been implicated as pathophysio-logical mediators of obesity and insulin resistance and are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme regenerates active Corticosterone from inactive 11-keto forms. To assess the role of 11β-HSD1-mediated synthesis of active cor-ticosterone in leptin-related obesity and diabetes, we examined the peripheral effect of leptin on 11β-HSD1 activity and gene expression in vivo and in vitro in hepatocytes from ob/ob mice and in liver of streptozo-tocin (STZ)-treated oblob mice. We observed an inverse relationship between hepatic 11β-HSD1 expression and body weight in oblob mice and lean littermates. Leptin treatment of ob/ob mice markedly increased hepatic 11β-HSD1 activity and mRNA expression. This induction of 11β-HSD1 expression corresponded to reduced levels of circulating Corticosterone and weight loss in ob/ob mice treated with leptin, indicating that impaired hepatic 11β-HSD1 expression may contribute to the pathogenesis of obesity in ob/ob mice. In addition, leptin treatment of STZ-treated ob/ob mice caused marked increases in hepatic 11β-HSD1 levels associated with decreased body weight and a significant reduction in hyperglycemia due to pancreatic β-cell damage. Addition of leptin to ob/ob mouse primary hepatocytes led to a dose-dependent increase in 11β-HSD1 mRNA expression. In contrast, leptin did not influence 11β-HSD1 expression in primary hepatocytes from db/db mice, indicating that leptin regulation of 11β-HSD1 expression is probably mediated by the functional leptin receptor. Thus, leptin appears to be an important metabolic signal that directly activates intrahepatic corticoste-rone production. These findings suggest that the liver-specific interaction of leptin with 11β-HSD1 is involved in the development of obesity and insulin resistance in ob/ob mice.