NF-κB-inducing kinase maintains mitochondrial efficiency and systemic metabolic homeostasis.
NF-κB-inducing kinase maintains mitochondrial efficiency and systemic metabolic homeostasis.
复制标题
NF-κB 诱导激酶维持线粒体效率和全身代谢稳态。
DOI：
10.1016/j.bbadis.2023.166682
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Sitcheran,Raquel
中科院分区：
文献类型：
--
作者：
Pflug,KathrynM;Lee,DongW;Keeney,JustinN;Sitcheran,Raquel
NF-κ B诱导激酶（NIK）是非经典NF-κB信号的重要上游诱导因子，是免疫和炎症的重要调节因子。我们最近的工作表明，NIK调节癌症和先天免疫细胞中的线粒体呼吸和适应性代谢反应。然而，目前尚不清楚NIK是否也具有调节全身代谢的作用。在这项研究中，我们证明了NIK对发育和代谢过程具有局部和全身作用。我们的研究结果表明，NIK缺陷小鼠表现出减少的肥胖，以及基础和高脂肪饮食压力下的能量消耗增加。此外，我们确定NF-κ B的非依赖性和依赖性功能的NIK在白色脂肪组织的代谢和发展。具体地说，我们发现NIK以NF-κ B非依赖性的方式是维持线粒体健康所必需的，因为NIK缺陷的脂肪细胞具有受损的线粒体膜电位和备用呼吸能力。除了线粒体耗竭外，NIK缺陷型脂肪细胞和活体脂肪组织还表现出糖酵解的代偿性上调，以满足生物能量需求。最后，虽然NIK对前脂肪细胞线粒体代谢的调节是NF-κ B非依赖性的，但我们证明NIK在脂肪细胞分化中具有补充作用，需要激活RelB和非经典NF-κB途径。总的来说，这些数据表明，NIK在局部和全身发育和代谢中具有关键作用。我们的研究结果建立了NIK作为一个重要的调节器的细胞器，细胞和全身代谢稳态，这表明代谢功能障碍可能是一个重要的和不受重视的组成部分，免疫紊乱和炎症性疾病所产生的NIK缺乏症。
NF-κB-inducing kinase (NIK) is an essential upstream inducer of noncanonical NF-κB signaling and a critical regulator of immunity and inflammation. Our recent work has demonstrated that NIK regulates mitochondrial respiration and adaptive metabolic responses in cancer and innate immune cells. However, it is not clear whether NIK also has roles in regulating systemic metabolism. In this study, we demonstrate that NIK has local and systemic effects on developmental and metabolic processes. Our findings show that NIK-deficient mice exhibit reduced adiposity, as well as elevated energy expenditure both basally, and under the stress of a high-fat diet. Moreover, we identify NF-κB-independent and -dependent functions for NIK in white adipose tissue metabolism and development. Specifically, we found that in an NF-κB-independent manner NIK is required for maintaining mitochondrial fitness, as NIK-deficient adipocytes have impaired mitochondrial membrane potential and spare respiratory capacity. In addition to mitochondrial exhaustion, NIK-deficient adipocytes andex vivoadipose tissue exhibit a compensatory upregulation of glycolysis to meet bioenergetic demands. Finally, while NIK regulation of mitochondrial metabolism in preadipocytes is NF-κB-independent, we demonstrate that NIK has a complementary role in adipocyte differentiation that requires activation of RelB and the noncanonical NF-κB pathway. Collectively, these data demonstrate that NIK has critical roles in local and systemic development and metabolism. Our findings establish NIK as an important regulator of organelle, cell, and systemic metabolic homeostasis, suggesting that metabolic dysfunction may be an important and unappreciated component of immune disorders and inflammatory diseases arising from NIK deficiency.