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Diabetes 52:1409-1416, 2003
© 2003 by the American Diabetes Association, Inc.

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

Yanjun Liu1,2, Yuichi Nakagawa2, Ying Wang3, Renshan Li2, Xiaojun Li4, Takehiko Ohzeki2, and Theodore C. Friedman1

1 Division of Endocrinology, Charles R. Drew University of Medicine & Sciences, UCLA School of Medicine, Los Angeles, California
2 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
3 Department of Internal Medicine, Division of Laboratory Research and Development, Charles R. Drew University of Medicine & Sciences, UCLA School of Medicine, Los Angeles, California
4 Department of Cardiology, Cedars-Sinai Medical Center, University of California, Los Angeles, Los Angeles, California

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


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