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。最近的数据 表明肥胖和胰岛素抵抗之间存在炎症联系。该提案将侧重于适应性 在热量过载和限制期间能量消耗的变化，并探索一种新的假设， 直接导致新的治疗方法。我们假设蛋白质的激活和诱导 肥胖和禁食中的激酶TBK 1重编程代谢以促进合成代谢和抑制分解代谢 路径，将尺度转向能量储存，远离支出。这些结论是由 从小鼠基因敲除小鼠和接受TBK 1抑制剂氨来沙诺治疗的患者中观察到的变化。 具体而言，TBK 1的激活或诱导抑制AMPK活性，抑制脂质氧化和 线粒体生物合成，同时增加脂肪生成。我们将探讨这个假设有三个目标：1）我们 将评估肥胖期间TBK 1激活和诱导的时间和空间方面， 表征潜在机制; 2）我们将探索禁食期间TBK 1的激活和诱导， 3）探讨TBK 1/AMPK轴在调控细胞凋亡中的作用。 通过开发化合物敲除小鼠模型来研究肥胖和禁食期间的代谢，并评估 这一规定的时间和空间方面。这些发现可能揭示了能量消耗是如何 抑制期间热量过剩和限制，并提供新的治疗方法，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.