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- Title
Inhibition of Hepatic Glucocorticoid Availability in Response to the Development of Diet Induced Obesity and Insulin Resistance in Mice.
- Authors
Liu, Yanjun; Wang, Ying; Nakagawa, Yuichi; Chen, Li; Ren, Xiuhai; Friedman, Theodore C.
- Abstract
11beta-hydroxysteroid dehydrogenase type 1 regenerates active corticosterone from inactive 11-dehydrocorticosterone. Inhibition of tissue glucocorticoid (GC) availability by 1lbeta-HSD1 inhibitors may improve insulin resistance and obesity associated with type 2 diabetes and metabolic syndrome. To assess the functional role of tissue GC regeneration in the development of obesity and type 2 diabetes, we examined the possible effects of 11beta-HSD1 inhibitor carbenoxolone (CBX) in vivo and in vitro in hepatocytes from diet-induced obese (DIO) mice. Chronic treatment of DIO mice with CBX markedly decreased the expression of both 11 beta-HSD1 reductase activity and its mRNA expression in liver and improved the insulin sensitivity and obesity despite CBX suppression of 11beta-HSD1 dehydrogenase activity in kidney. Suppression of hepatic 11beta-HSD1 expression was correlated with reduced levels of blood glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase (PEPCK) mRNA in liver. Treatment of mouse primary hepatocytes with CBX resulted in significant inhibition of both 11beta-HSD1 reductase activity and its mRNA expression. Addition of CBX to primary hepatocytes also suppressed the effects of corticosterone-induced 11 beta-HSD1 reductase activity and attenuated the increased PEPCK mRNA expression. These findings suggest that CBX is able to effectively inhibit the generation of active glucocorticoid in mouse liver and exerts functional consequences including decreased the diet-induced insulin resistance and obesity in mice.
- Publication
Diabetes, 2007, Vol 56, pA457
- ISSN
0012-1797
- Publication type
Academic Journal