Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.
Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.
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DOI：
10.1038/ncomms12205
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发表时间：
2016-07-27
影响因子：
16.6
通讯作者：
Kuang S
中科院分区：
文献类型：
--
作者：
Shan T;Xiong Y;Zhang P;Li Z;Jiang Q;Bi P;Yue F;Yang G;Wang Y;Liu X;Kuang S
棕色脂肪组织（BAT）通过Ucp 1介导的解偶联呼吸消耗能量，其激活可能代表了对抗肥胖的治疗策略。在这里，我们表明，Lkb 1控制BAT的扩张和UCP 1在小鼠中的表达。我们产生了脂肪细胞特异性Lkb 1基因敲除小鼠，并表明，与野生型同窝小鼠相比，这些小鼠在BAT和皮下白色脂肪组织中表现出升高的UCP 1表达，BAT质量增加，能量消耗增加。因此，KO小鼠具有改善的葡萄糖耐量和胰岛素敏感性，并且对高脂饮食（HFD）诱导的肥胖更有抵抗力。在棕色脂肪细胞中，Lkb 1的缺失导致CRTC 3从细胞质易位到细胞核，在那里它募集C/EBPβ以增强Ucp 1的转录。同时，Lkb 1的缺失也抑制AMPK活性，导致mTOR信号通路的激活和随后的BAT扩增。这些数据表明，抑制脂肪细胞中的Lkb 1或其下游信号传导可能是在肥胖、糖尿病和其他代谢疾病的背景下增加能量消耗的新策略。 激酶Lkb 1在各种代谢组织中表达，并且已知调节细胞和全身能量稳态。在这里，作者删除了Lkb 1特异性在成熟的小鼠脂肪细胞，以表明Lkb 1调节棕色脂肪组织扩张和UCP 1的表达。
Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity. Deletion of Lkb1 results in a cytoplasm to nuclear translocation of CRTC3 in brown adipocytes, where it recruits C/EBPβ to enhance Ucp1 transcription. In parallel, the absence of Lkb1 also suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion. These data suggest that inhibition of Lkb1 or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases. The kinase Lkb1 is expressed in various metabolic tissues and is known to regulate cellular and systemic energy homeostasis. Here, the authors delete Lkb1 specifically in mature adipocytes of mice to show that Lkb1 regulates brown adipose tissue expansion and expression of UCP1.