Antisense reduction of 11β-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet.
Antisense reduction of 11β-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet.
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DOI：
10.1016/j.metabol.2011.11.008
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发表时间：
2012-06
影响因子：
9.8
通讯作者：
Ginsberg, Henry N.
中科院分区：
文献类型：
--
作者：
Li, Guoping;Hernandez-Ono, Antonio;Crooke, Rosanne M.;Graham, Mark J.;Ginsberg, Henry N.
我们最近报道用反义寡核苷酸抑制11β-羟基类固醇脱氢酶1(11β-HSD1)可以改善肝脏的脂代谢，而不依赖于食物的摄入量。在这项研究中，11只β-HSD1ASO处理的小鼠与食物匹配的对照ASO处理的小鼠相比体重减轻，这表明治疗介导的能量消耗增加。我们现在已经检查了11个β-HSD1ASO治疗对脂肪组织代谢、胰岛素敏感性和全身能量消耗的影响。我们用反义寡核苷酸敲除了C57BL/6J小鼠中11个β-HSD1基因。11只β-HSD1反义寡核苷酸处理的小鼠摄入的食物较少，因此食物匹配的对照反义寡核苷酸处理的小鼠也被评估。我们确定了身体组成、个体脂肪储存库的基因表达以及能量代谢的指标。我们还研究了几个组织中的葡萄糖/胰岛素耐量以及急性胰岛素信号。敲除11个β-hsd1基因可以减少附睾部、肠系膜和皮下白色脂肪组织(WAT)，同时激活棕色脂肪组织(BAT)的产热，从而预防由WTD引起的肥胖。在11只β-HSD1ASO处理的小鼠中，能量消耗增加证实了后者。11β-HSD1反义寡核苷酸治疗还能保护小鼠免受外周血糖耐量异常和胰岛素抵抗的影响；这种保护作用与附睾水中较小的细胞和较少的巨噬细胞有关，以及体内胰岛素信号的增强。我们的结果表明，ASO介导的对11β-HSD1的抑制可以预防WTD诱导的几种代谢异常。这些影响至少在一定程度上是由BAT氧化能力的增加所介导的。
We recently reported that inhibition of 11beta-hydroxysteroid dehydrogenases 1 (11β-HSD1) by antisense oligonucleotide (ASO) improved hepatic lipid metabolism independent of food intake. In that study, 11β-HSD1 ASO-treated mice lost weight compared to food matched control ASO-treated mice, suggesting treatment-mediated increased energy expenditure. We have now examined the effects of 11β-HSD1 ASO treatment on adipose tissue metabolism, insulin sensitivity, and whole body energy expenditure. We used an ASO to knockdown 11β-HSD1in C57BL/6J mice consuming a Western-type diet (WTD). 11β-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 11β-HSD1 protected against WTD-induced obesity by reducing epididymal, mesenteric, and subcutaneous white adipose tissue (WAT) while activating thermogenesis in brown adipose tissue (BAT). The latter was confirmed by demonstrating increased energy expenditure in 11β-HSD1 ASO treated mice. 11β-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 WAT as well as enhanced in vivo insulin signaling. Our results indicate that ASO-mediated inhibition of 11β-HSD1 can protect against several WTD-induced metabolic abnormalities. These effects are, at least in part, mediated by increases in the oxidative capacity of BAT.
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DOI：
10.1152/ajpendo.00276.2007
发表时间：
2007-10-01
影响因子：
5.1
作者：
Berthiaume, Magalie;Laplante, Mathieu;Deshaies, Yves
通讯作者：
Deshaies, Yves
影响因子：
29
作者：
Lemke, Ulrike;Krones-Herzig, Anja;Herzig, Stephan
通讯作者：
Herzig, Stephan
影响因子：
6.9
作者：
Lee, Mi-Jeong;Fried, Susan K.;Hermanowski-Vosatka, Anne
通讯作者：
Hermanowski-Vosatka, Anne
影响因子：
4.8
作者：
Morton, NM;Holmes, MC;Seckl, JR
通讯作者：
Seckl, JR
影响因子：
5.8
作者：
Lloyd, D. J.;Helmering, J.;Veniant, M. M.
通讯作者：
Veniant, M. M.