Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA.
Cell. 2018 Feb 8;172(4):731-743.e12. doi: 10.1016/j.cell.2018.01.007.
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-κB activity. Moreover, TBK1 mediates the negative impact of AMPK activity on NF-κB 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.
非典型 IKK 家族成员 TANK 结合激酶 1（TBK1）被促炎细胞因子激活，但它在控制代谢中的作用尚不清楚。在这里，我们报告说该激酶独特地控制着能量代谢。高脂肪饮食喂养的小鼠脂肪细胞中 TBK1 的表达增加。脂肪细胞特异性 TBK1 敲除（ATKO）通过增加能量消耗来减轻高脂肪饮食诱导的肥胖；进一步的研究表明，TBK1 直接抑制 AMPK 以抑制呼吸并增加能量储存。相反，在分解代谢条件下激活 AMPK 可以通过磷酸化来增加 TBK1 的活性，这由 AMPK 的下游靶标 ULK1 介导。令人惊讶的是，ATKO 还会加剧脂肪组织炎症和胰岛素抵抗。TBK1 通过磷酸化和诱导 IKK 激酶 NIK 的降解来抑制炎症，从而减弱 NF-κB 活性。此外，TBK1 介导了 AMPK 活性对 NF-κB 激活的负面影响。这些数据表明，TBK1 在调节营养过剩和不足时能量感应和炎症信号通路之间的双向串扰中具有独特的作用。
