Regulating energy expenditure in adipose tissue

摘要 毫无疑问，我们正处于肥胖和糖尿病的全球流行之中。最新数据 表明肥胖和胰岛素抵抗之间存在炎症联系。这项提案将重点放在适应性 在卡路里超载和限制期间能量消耗的变化，并探索一个新的假设，可能 直接导致新的治疗方法。我们假设蛋白质的激活和诱导 蛋白酪氨酸激酶1在肥胖和空腹代谢中促进合成代谢和抑制分解代谢 路径，使天平向储能倾斜，而不是支出。这些结论是由 根据在小鼠基因敲除小鼠和接受TBK1抑制剂氨来昔诺治疗的患者中观察到的变化。 具体地说，激活或诱导TBK1抑制AMPK活性，抑制脂质氧化和 线粒体的生物发生同时增加脂肪的生成。我们将以三个目标来探讨这一假设：1)我们 将评估肥胖期间TBK1的激活和诱导的时间和空间方面，以及 2)我们将探索禁食过程中TBK1的激活和诱导， 3)我们将评估TBK1/AMPK轴在调控中的作用 通过建立复合基因敲除小鼠模型研究肥胖和禁食期间的代谢，并进行评估 这一规定的时间和空间方面。这些发现可能会揭示能量消耗是如何 在卡路里过量和限制期间被抑制，并为这些毁灭性的 疾病。

Abstract There is little doubt that we are in the midst of a worldwide epidemic of obesity and diabetes. Recent data suggest an inflammatory link between obesity and insulin resistance. This proposal will focus on adaptive changes in energy expenditure during caloric overload and restriction, and explore a novel hypothesis that may directly lead to new therapeutic approaches. We hypothesize that that activation and induction of the protein kinase TBK1 in obesity and fasting reprograms metabolism to promote anabolic and repress catabolic pathways, tipping the scales towards energy storage and away from expenditure. These conclusions are derived from changes observed in mouse knockout mice, and in patients treated with the TBK1 inhibitor amlexanox. Specifically, activation or induction of TBK1 represses AMPK activity, inhibiting lipid oxidation and mitochondrial biogenesis while increasing lipogenesis. We will explore this hypothesis with three aims: 1) We will evaluate the temporal and spatial aspects of TBK1 activation and induction during obesity, and characterize the underlying mechanism; 2) We will explore the activation and induction of TBK1 during fasting, and elucidate the molecular mechanisms; 3) We will assess the role of the TBK1/AMPK axis in controlling metabolism during obesity and fasting via development of compound knockout mouse models, and evaluate the temporal and spatial aspects of this regulation. These findings may reveal how energy expenditure is repressed during caloric excess and restriction, and provide new therapeutic approaches to these devastating diseases.