TAK1 regulation of metabolism

 描述(申请人提供)：能量代谢受到严格调控，代谢稳态的破坏可能导致代谢综合征，如肥胖症和II型糖尿病。炎症是能量新陈代谢的一个重要干扰因素。因此，了解炎症诱导的代谢紊乱的分子途径对于防治代谢性疾病至关重要。炎症信号分子如c-jun氨基末端激酶和核因子-κB被认为是代谢性疾病的介质。JNK和NF-κB抑制胰岛素受体底物1，胰岛素受体底物1是包括肝脏和脂肪组织在内的几个组织中胰岛素抵抗的原因。除了依赖jnk和nf-κB的机制外，新的证据表明内质网应激是连接炎症和代谢紊乱的主要途径。然而，炎症诱导内质网应激的分子机制尚不清楚。我们发现，蛋白激酶TAK1的缺失可以保护细胞免受内质网应激的影响，而神经元特异性的TAK1缺失可以阻止炎症相关的代谢紊乱，包括超重增加。TAK1属于丝裂原活化蛋白激酶(MAP3K)家族，是炎症信号通路的中间体。TAK1可激活JNK和NF-κB，而Tak1缺失对JNK和NF-κB的活性无明显影响。因此，TAK1通过一条以前未知的途径来调节内质网应激和能量代谢。为了确定TAK1的一个新的下游途径，我们发现TAK1抑制转录因子SREBP，而SREBP是脂肪形成的关键调节因子。脂肪生成是膜生物发生的重要环节，它的改变影响内质网的质量和功能。我们推测，炎症诱导的TAK1激活通过抑制SREBP依赖的脂肪生成而下调膜生物发生，这与内质网应激和全身能量代谢的神经元调节紊乱有关。在这个项目中，我们将描述：1)TAK1调节脂肪生成的分子机制；2)TAK1-脂肪生成途径在内质网应激中的作用；3)神经元TAK1-脂肪生成-ER应激途径与全身代谢紊乱之间的联系。该项目的结果将揭示炎症和能量代谢之间的新的机制联系。

 DESCRIPTION (provided by applicant): Energy metabolism is tightly regulated, and disruptions in the metabolic homeostasis could lead to metabolic syndromes such as obesity and type II diabetes. Inflammation is a prominent disrupter of energy metabolism. Thus, understanding molecular pathways of inflammation-induced metabolic disorders is critical to combat metabolic diseases. Inflammatory signaling molecules such as c-Jun N-terminal kinase (JNK) and NF-κB have been identified as mediators of metabolic diseases. JNK and NF-κB inhibit insulin receptor substrate 1, which is responsible for insulin resistance in several tissue including liver and adipose tissues. In addition to the JNK- and NF-κB-dependent mechanisms, emerging evidence indicates that endoplasmic reticulum (ER) stress is the major pathway linking inflammation and metabolic disorders. However, the molecular mechanism by which inflammation induces ER stress is not yet clear. We found that deletion of a protein kinase TAK1 protects cells from ER stress, and that neuron-specific TAK1 deletion blocks inflammation associated metabolic disorders including excess weight gain. TAK1 belongs to the mitogen-activated protein kinase kinase kinase (MAP3K) family, and is an intermediate of inflammatory signaling pathways. TAK1 can activate JNK and NF-κB; however, activity of JNK and NF-κB is unaltered in the deletion of Tak1 in neurons. Thus, TAK1 modulates ER stress and energy metabolism through a previously uncharacterized pathway. In an effort to determine a new downstream pathway of TAK1, we have found that TAK1 inhibits a transcription factor SREBP, which is the key regulator of lipogenesis. Lipogenesis is important for membrane biogenesis and its alteration impacts the ER mass and function. We hypothesize that inflammation-induced TAK1 activation downregulates membrane biogenesis through inhibiting SREBP-dependent lipogenesis, which is causally associated with ER stress and the disorder in neuronal regulation of systemic energy metabolism. In this project, we will delineate: 1) the molecular mechanism by which TAK1 modulates lipogenesis, 2) the role of TAK1-lipogenesis pathway in ER stress, and 3) the link between neuronal TAK1-lipogenesis-ER stress pathway and systemic metabolic disorders. Outcomes of this project will reveal a new mechanistic link between inflammation and energy metabolism.