TAK1 regulation of metabolism

 描述（由申请人提供）：能量代谢受到严格调节，代谢稳态的破坏可能导致代谢综合征，如肥胖和II型糖尿病。炎症是能量代谢的一种重要破坏因素。因此，了解炎症诱导的代谢紊乱的分子途径对于对抗代谢疾病至关重要。炎症信号分子如c-Jun N-末端激酶（JNK）和NF-κB已被鉴定为代谢性疾病的介质。JNK和NF-κB抑制胰岛素受体底物1，其负责包括肝脏和脂肪组织在内的若干组织中的胰岛素抵抗。除了JNK和NF-κ B依赖性机制外，新的证据表明内质网（ER）应激是连接炎症和代谢紊乱的主要途径。然而，炎症诱导ER应激的分子机制尚不清楚。我们发现，蛋白激酶TAK 1的缺失保护细胞免受ER应激，并且神经元特异性TAK 1缺失阻断炎症相关的代谢紊乱，包括过度体重增加。TAK 1属于丝裂原活化蛋白激酶（MAP 3 K）家族，是炎症信号通路的中间体。Tak 1可激活JNK和NF-κB，但Tak 1缺失后，JNK和NF-κB活性无明显变化。因此，TAK 1通过以前未表征的途径调节ER应激和能量代谢。为了确定TAK 1的新下游通路，我们发现TAK 1抑制转录因子SREBP，这是脂肪生成的关键调节因子。脂肪生成对于膜生物合成是重要的，其改变影响ER的质量和功能。我们推测炎症诱导的TAK 1激活通过抑制SREBP依赖的脂肪生成来下调膜生物合成，这与ER应激和全身能量代谢的神经元调节障碍有因果关系。本课题主要研究TAK 1调控脂肪生成的分子机制、TAK 1-脂肪生成途径在内质网应激中的作用以及神经元TAK 1-脂肪生成-内质网应激途径与全身代谢紊乱的关系。该项目的结果将揭示炎症和能量代谢之间的新机制联系。

 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.