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Am J Physiol Endocrinol Metab 292: E1213-E1222, 2007. First published December 26, 2006; doi:10.1152/ajpendo.00340.2006
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Bezafibrate regulates the expression and enzyme activity of 11-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes

¹Pharmacology Research Laboratory R&D, and ³Development Research Department R&D, Kissei Pharmaceutical, Nagano; and ²Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan

Submitted 13 July 2006 ; accepted in final form 20 December 2006

A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(, -, and -) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11-HSD1 preferentially in adipose tissue of db/db mice (–47%, P < 0.05), concomitant with a significant increase in plasma adiponectin level (+37%, P < 0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (–34%, P < 0.01) and enzyme activity (–32%, P < 0.01) of 11-HSD1, whereas the treatment substantially augmented the expression (+71%, P < 0.01) and secretion (+27%, P < 0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11-HSD1 by siRNA confirmed that 11-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolically-beneficial effects by bezafibrate.

metabolic syndrome; adiponectin

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