ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue.
ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue.
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DOI：
10.1016/j.celrep.2014.10.066
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发表时间：
2014-12-11
期刊：
影响因子：
8.8
通讯作者：
Kajimura S
中科院分区：
文献类型：
--
作者：
Galmozzi A;Sonne SB;Altshuler-Keylin S;Hasegawa Y;Shinoda K;Luijten IHN;Chang JW;Sharp LZ;Cravatt BF;Saez E;Kajimura S
当能量摄入长期超过能量消耗时，肥胖就会发生。由于棕色脂肪组织(BAT)以热的形式消耗能量，因此通过加强BAT介导的产热来增加能量消耗可能是一种对抗肥胖及其并发症的方法。BAT的能量耗散能力依赖于线粒体解偶联蛋白1(UCP1)的表达。为了便于确定可能作为减肥药物的BAT UCP1水平的药理调节因子，我们开发了一种转基因模型，在该模型中，荧光素酶活性忠实地模拟内源性UCP1的表达及其对生理刺激的反应。使用来自该模型的细胞对文库进行表型筛选，发现了一种小分子，它增加了棕色脂肪细胞和小鼠中UCP1的表达。在肾上腺素能刺激下，复合治疗组小鼠表现出更多的能量消耗。这些工具提供了一个机会来识别UCP1表达的药理调节因子，并发现影响BAT介导的产热的新的调控途径。
Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial protein Uncoupling Protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as anti-obesity medications, we have developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small-molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover new regulatory pathways that impact BAT-mediated thermogenesis.
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影响因子：
7.7
作者：
Saito M;Okamatsu-Ogura Y;Matsushita M;Watanabe K;Yoneshiro T;Nio-Kobayashi J;Iwanaga T;Miyagawa M;Kameya T;Nakada K;Kawai Y;Tsujisaki M
通讯作者：
Tsujisaki M
影响因子：
64.8
作者：
Gerhart-Hines Z;Feng D;Emmett MJ;Everett LJ;Loro E;Briggs ER;Bugge A;Hou C;Ferrara C;Seale P;Pryma DA;Khurana TS;Lazar MA
通讯作者：
Lazar MA
影响因子：
64.5
作者：
Fedorenko A;Lishko PV;Kirichok Y
通讯作者：
Kirichok Y
影响因子：
18.2
作者：
Kajimura S;Saito M
通讯作者：
Saito M
影响因子：
4.8
作者：
Golozoubova, V;Hohtola, E;Nedergaard, J
通讯作者：
Nedergaard, J