《Cell》:肥胖不全是你的错,TBK1要背锅

在啮齿动物模型和人类中的许多研究表明,肥胖在脂肪组织中产生慢性炎症,这种炎症是通过免疫细胞的募集和活化产生的,特别是促炎性巨噬细胞。而脂肪组织中的免疫细胞分泌的促炎细胞因子破坏了脂肪细胞中的胰岛素作用,继而导致胰岛素抵抗和2型糖尿病。


众所周知,在炎症反应中,非典型IKK家族系统成员TANK-结合激酶(TBK1)具有关键作用,它可被促炎激酶激活,激发一系列炎症反应,而TBK1在控制糖代谢和能量代谢中的作用还不得而知。近日,《CELL》发布一篇研究揭示了TBK1在控制代谢中的重要位置。


提到代谢不得不提到一个关键性蛋白激酶- AMP激活的蛋白激酶(AMPK),AMPA的激活能够促进卡路里的燃烧,较少脂肪堆积。


AMPA


•它是一种异源三聚体蛋白,通过AMPKa亚基中Thr172的磷酸化作用,可被肝脏激酶B1(LKB1)激活。

•可通过感应增加的AMP / ATP比例,响应于能量应激而被变构激活。

•激活AMPK可增加脂质氧化,抑制脂肪生成,并通过过氧化物酶体增殖物激活受体γ辅激活物1a(PGC1a)显着增加线粒体生物合成。

•AMPK还通过磷酸化和激活Unc-51样自噬激活激酶1(ULK1)来增加自噬,

•AMPK / ULK1轴是维持线粒体内稳态所必需的

•研究已经证实AMPK活性降低与炎症增加之间的相关性,而AMPK的活化降低促炎介质的表达并减弱炎症


而AMPA恰好是TBK1的下游靶蛋白,所以,肥胖极有可能是通过炎症反应,促进TBK1的表达,从而抑制AMPA激酶,降低能量代谢,引起脂肪堆积。


首先研究者检测了高脂喂养(HFD)的喂养的小鼠脂肪细胞中Tbk1表达水平,果不其然,其表达水平明显增加。而进一步的研究表明,AMPK是TBK1的直接底物,而且TBK1介导肿瘤坏死因子α(TNF-α)也可诱导的AMPK活性抑制,增加能量储存。


然后,研究者特异性(ATKO)敲除了脂肪细胞中TBK1后,肥胖小鼠的肥胖症状得到了缓解。但是,令人惊讶的是,ATKO后,AMPK的激活通过AMPK的下游靶标ULK1介导的磷酸化反而又提高TBK1活性,使脂肪组织炎症和胰岛素抵抗增强。


这些数据暗示了TBK1在过度营养和营养不足中介导能量感应和炎症信号途径之间的双向串扰的独特作用。


当食物摄入量超过能量消耗时,肥胖会产生正能量平衡。尽管能量摄入和支出紧密结合以保证体内平衡,但随着时间的推移,即使轻微的不匹配也会导致体重增加和葡萄糖耐受不良。 尽管短期的营养过剩与啮齿类动物和人类的能量消耗增加有关,但是持续的肥胖会降低能量消耗,限制热量也会降低能量消耗,导致基础代谢率降低,从而捍卫体重。


因此,营养过剩和营养不良都与能源消耗减少有关。通过控制饮食摄入,并同时抑制TBK1来解放细胞燃烧卡路里能力,我们才有望迎来更有效的减肥效果。


SUMMARY

The noncanonical IKK family member TANK-binding kinase 1 (TBK1) is activated by pro-inflammatory

cytokines, but its role in controlling metabolism remains unclear. Here, we report that the kinase

uniquely controls energy metabolism. Tbk1 expression is increased in adipocytes of HFD-fed mice.

Adipocyte-specific TBK1 knockout (ATKO) attenuates HFD-induced obesity by increasing energy

expenditure; further studies show that TBK1 directly inhibits AMPK to repress respiration and increase energy storage. Conversely, activation of AMPK under catabolic conditions can increase TBK1 activity through phosphorylation, mediated by AMPK’s downstream target ULK1. Surprisingly, ATKO also exaggerates adipose tissue inflammation and insulin resistance. TBK1 suppresses inflammation by phosphorylating and inducing the degradation of the IKK kinase NIK, thus attenuating NF-kB activity. Moreover, TBK1 mediates the negative impact of AMPK activity on NF-kB activation. These data implicate a unique role for TBK1 in mediating bidirectional crosstalk between energy sensing and inflammatory signaling pathways in both over- and undernutrition.


RESULTS

• Adipocyte-Specific TBK1 Deficiency Increases Energy Expenditure and Attenuates HFD-Induced Obesity

• TBK1 Deficiency Upregulates Mitochondrial Biogenesis by Attenuating the Inflammation-Induced Inhibition of AMPK Activity in Adipose Tissues in Mice on a HFD

• TBK1 Directly Phosphorylates AMPK a Subunit to Inhibit AMPK Actsivity

• TBK1 Is Stimulated by Activation of AMPK

• Adipocyte-Specific TBK1 KO Mice Have Exaggerated HFD-Induced Glucose Intolerance and Insulin Resistance, along with Increased Adipose Inflammation

• Loss of TBK1 Increases TNF-a-Induced NF-Kb Activation in HFD-Fed Mice

• TBK1 Deficiency Attenuates Inhibition of NF-kB Signaling by AMPK

 

end

 

REFERENCES

http://www.cell.com/cell/fulltext/S0092-8674(18)30042-4


Powered by 上海翼石信息科技有限公司 © 2001-2016 dayibian Inc.
沪ICP备12046386号-1