Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide.
Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide.
复制标题
DOI：
10.1016/j.ejphar.2009.08.022
复制
发表时间：
2009-10-12
影响因子：
5
通讯作者：
Kensler, Thomas W.
中科院分区：
文献类型：
--
作者：
Shin, Soona;Wakabayashi, Junko;Yates, Melinda S.;Wakabayashi, Nobunao;Dolan, Patrick M.;Aja, Susan;Liby, Karen T.;Sporn, Michael B.;Yamamoto, Masayuki;Kensler, Thomas W.
合成齐墩果酸三萜1-[2-氰基-3,12-二氧齐墩烷-1,9(11)-二烯-28-油基]咪唑（CDDO-Imidazolide或CDDO-Im）是一种非常有效的Nrf2信号激活剂。在发生脂肪形成的细胞中，CDDO-Im以nrf2依赖的方式阻止脂质积累。然而，缺乏体内证据证明CDDO-Im对肥胖的影响。这些研究的目的是确定CDDO-Im是否可以预防小鼠高脂肪饮食诱导的肥胖发生，并阐明药物作用的分子靶点。野生型和nrf2破坏的C57BL/6J雌性小鼠每周灌胃3次30 μmol/kg CDDO-Im或对照物，连续95天饲喂对照或高脂饲料。测定体重、器官重量、肝脏脂肪积累和基因表达。在野生型小鼠中，用CDDO-Im治疗可以有效地防止高脂肪饮食引起的体重、脂肪量和肝脏脂质积累的增加，但在nrf2紊乱的小鼠中则没有。高脂肪饮食和CDDO-Im处理的野生型小鼠的耗氧量和能量消耗高于小鼠，而CDDO-Im处理的小鼠的食物摄入量低于小鼠。CDDO-Im处理后，野生型小鼠肝脏脂肪酸合成酶基因转录物水平下调。在nrf2干扰小鼠中，CDDO-Im对脂肪生成基因表达的抑制作用显著降低。结果表明，CDDO-Im是一种非常有效的预防肥胖的药物，并确定了Nrf2途径作为肥胖发生管理的新靶点。
The synthetic oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide or CDDO-Im) is an extremely potent activator of Nrf2 signaling. In cells undergoing adipogenesis, CDDO-Im prevents lipid accumulation in an Nrf2-dependent manner. However, in vivo evidence for effects of CDDO-Im on obesity is lacking. The goals of these studies were to determine if CDDO-Im can prevent high-fat diet-induced obesogenesis in the mouse, and to elucidate the molecular target of drug action. Wild-type and Nrf2-disrupted C57BL/6J female mice were dosed 3 times per week with 30 μmol/kg CDDO-Im or vehicle by oral gavage, during 95 days of access to a control diet or a high-fat diet. Body weights, organ weights, hepatic fat accumulation and gene expression were measured. Treatment with CDDO-Im effectively prevented high-fat diet-induced increases in body weight, adipose mass, and hepatic lipid accumulation in wild-type mice but not in Nrf2-disrupted mice. Wild-type mice on a high-fat diet and treated with CDDO-Im exhibited higher oxygen consumption and energy expenditure than vehicle-treated mice, while food intake was lower in CDDO-Im-treated than vehicle-treated mice. Levels of gene transcripts for fatty acid synthesis enzymes were downregulated after CDDO-Im treatment in the liver of wild-type mice. This inhibitory effect of CDDO-Im on lipogenic gene expression was significantly reduced in Nrf2-disrupted mice. The results indicate that CDDO-Im is an exceedingly potent agent for preventing obesity, and identify the Nrf2 pathway as a novel target for management of obesogenesis.
登录
查看更多内容
影响因子：
5.3
作者：
Shin, Soona;Wakabayashi, Nobunao;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
影响因子：
5.8
作者：
Weigle, DS
通讯作者：
Weigle, DS
DOI：
10.1073/pnas.201524598
发表时间：
2001-11-20
影响因子：
11.1
作者：
Yang, J;Goldstein, JL;Horton, JD
通讯作者：
Horton, JD
影响因子：
5.7
作者：
Yates, Melinda S.;Tauchi, Masafumi;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
通讯作者：
Talalay, P