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Nature Medicine:减少外周serotonin,促进BAT产热

  1. BAT
  2. serotonin
  3. 肥胖
  4. 脂肪酸胰岛素

来源:生物谷 2015-02-08 15:59

加拿大科学家发现抑制外周serotonin能够改变棕色脂肪细胞产热基因表达,改善小鼠肥胖及胰岛素抵抗等代谢综合征。
                                                        
2015年2月8日讯  /生物谷BIOON/  --近日,著名国际期刊Nature Medicine发表了加拿大科学家的一项最新研究成果,他们发现抑制外周serotonin能够改变棕色脂肪细胞产热基因表达,改善小鼠肥胖及胰岛素抵抗等代谢综合征。
 
研究人员指出,线粒体解偶联蛋白1(UCP1)在肩胛间棕色脂肪组织和米色脂肪组织中含量非常丰富,但在肥胖和II型糖尿病中,其促产热功能会发生下降,但原因仍不清楚。Serotonin是一种高度保守的生物胺,能在非神经组织和神经组织中发挥作用,并特异性受到Tph1和Tph2的分别调控。最近一些研究发现外周serotonin增加以及TPH1多态性与肥胖相关,但这是否与BAT产热功能下降以及肥胖直接相关仍不得而知。
 
通过实验发现,高脂饮食喂养的Tph1缺陷小鼠能够抵抗肥胖,胰岛素抵抗以及非酒精性脂肪肝发生,同时还出现棕色脂肪产热增加。在高脂饮食喂养的小鼠中用小分子化合物抑制Tph1能够模拟Tph1缺失小鼠的代谢获益效应,并且这种效应依赖于UCP1调节的产热。在体外实验中发现serotonin能够阻断β肾上腺素诱导的棕色脂肪和米色脂肪细胞产热基因表达,因此抑制serotonin导致的能量消耗增加是一种细胞自发性效应。肥胖能够增加外周serotonin水平,在脂肪组织中抑制serotonin信号或其合成可成为治疗肥胖及其并发症的一种有效方法。(生物谷Bioon.com)
 
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Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis
 
Justin D Crane, Rengasamy Palanivel, Emilio P Mottillo, Adam L Bujak, Huaqing Wang,Rebecca J Ford, Andrew Collins, Regje M Blümer, Morgan D Fullerton, Julian M Yabut,Janice J Kim, Jean-Eric Ghia, Shereen M Hamza, Katherine M Morrison, Jonathan D Schertzer, Jason R B Dyck, Waliul I Khan & Gregory R Steinberg
 
Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue1, 2, but its thermogenic potential is reduced with obesity and type 2 diabetes3, 4, 5 for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively6, 7, 8. Recent findings suggest that increased peripheral serotonin9 and polymorphisms in TPH1 are associated with obesity10; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.
 

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