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.

中文翻译：

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Lkb1通过调节CRTC3的细胞内定位来控制棕色脂肪组织的生长和生热。

棕色脂肪组织（BAT）通过Ucp1介导的非耦合呼吸耗散能量，其激活可能代表对抗肥胖的治疗策略。在这里，我们显示Lkb1控制小鼠中的BAT扩展和UCP1表达。我们生成脂肪细胞特异性Lkb1基因敲除小鼠，并表明，与野生型同窝仔相比，这些小鼠在BAT和皮下白色脂肪组织中表现出UCP1表达升高，BAT量增加，能量消耗更高。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）引起的肥胖症更具抵抗力。Lkb1的缺失导致棕色脂肪细胞中细胞质向CRTC3的核转运，从而募集C /EBPβ来增强Ucp1转录。同时，Lkb1的缺失也会抑制AMPK活性，导致mTOR信号通路的激活和随后的BAT扩展。这些数据表明，在肥胖，糖尿病和其他代谢性疾病的背景下，抑制Lkb1或其在脂肪细胞中的下游信号传导可能是增加能量消耗的新策略。