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

Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob / ob Mice Yanjun Liu 1 2 , Yuichi Nakagawa 2 , Ying Wang 3 , Renshan Li 2 , Xiaojun Li 4 , Takehiko Ohzeki 2 and Theodore C. Friedman 1 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 Abstract Glucocorticoids have been implicated as pathophysiological 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 corticosterone 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 streptozotocin (STZ)-treated ob / ob mice. We observed an inverse relationship between hepatic 11β-HSD1 expression and body weight in ob / ob 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 activat