Antisense reduction of 11 beta-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet

作者：Li Guoping; Hernandez Ono Antonio; Crooke Rosanne M; Graham Mark J; Gin**erg Henry N^*

来源：Metabolism-Clinical and Experimental, 2012, 61(6): 823-835.

DOI：10.1016/j.metabol.2011.11.008

We recently reported that inhibition of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) by antisense oligonucleotide (ASO) improved hepatic lipid metabolism independent of food intake. In that study, 11 beta-HSD1 ASO-treated mice lost weight compared with food-matched control ASO-treated mice, suggesting treatment-mediated increased energy expenditure. We have now examined the effects of 11 beta-HSD1 ASO treatment on adipose tissue metabolism, insulin sensitivity, and whole-body energy expenditure. We used an ASO to knock down 11 beta-HSD1 in C57BL/6J mice consuming a Western-type diet (WTD). The 11 beta-HSD1 ASO-treated mice consumed less food, so food-matched control ASO-treated mice were also evaluated. We characterized body composition, gene expression of individual adipose depots, and measures of energy metabolism. We also investigated glucose/insulin tolerance as well as acute insulin signaling in several tissues. Knockdown of 11 beta-HSD1 protected against WTD-induced obesity by reducing epididymal, mesenteric, and subcutaneous white adipose tissue while activating therrnogenesis in brown adipose tissue. The latter was confirmed by demonstrating increased energy expenditure in 11 beta-HSD1 ASO-treated mice. The 11 beta-HSD1 ASO treatment also protected against WTD-induced glucose intolerance and insulin resistance; this protection was associated with smaller cells and fewer macrophages in epididymal white adipose tissue as well as enhanced in vivo insulin signaling. Our results indicate that ASO-mediated inhibition of 11 beta-HSD1 can protect against several WTD-induced metabolic abnormalities. These effects are, at least in part, mediated by increases in the oxidative capacity of brown adipose tissue.

• 出版日期2012-6