Regulating energy expenditure in adipose tissue

调节脂肪组织的能量消耗

基本信息

批准号：
10434151
负责人：
ALAN R. SALTIEL
金额：
$ 54.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434151
关键词：
Acute Adipocytes Adipose tissue Attenuated Binding Biogenesis Body Weight decreased Brown Fat Caloric Restriction Catecholamines Data Development Diabetes Mellitus Disease Effectiveness Energy Metabolism Enzymes Epidemic Event Expenditure FOXO1A gene Famines Fasting Fatty Liver Feedback Gene Expression Genetic Transcription High Fat Diet Homeostasis In Vitro Inflammation Inflammatory Insulin Insulin Resistance Knockout Mice Lead Link Lipids Longitudinal Studies Mediating Messenger RNA Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Molecular Mus Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Obesity Epidemic Pathway interactions Patients Phosphorylation Phosphorylation Site Phosphotransferases Physiological Protein Kinase Regulation Role Scaffolding Protein Starvation TBK1 gene Time Transcriptional Regulation Uncertainty amlexanox attenuation combat dieting in vivo inhibitor insight interest lipid biosynthesis liver inflammation mouse model novel novel strategies novel therapeutic intervention obese patients oxidation preservation promoter restoration

项目摘要

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.

抽象的毫无疑问，我们正处于肥胖和糖尿病的全球流行病中。最新数据提出肥胖与胰岛素抵抗之间的炎症联系。该建议将重点放在适应性上热量超负荷和限制期间能量消耗的变化，并探索一个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激酶TBK1在肥胖和禁食重编程中代谢，以促进合成代谢和抑制分解代谢途径，将秤倾斜到储能，并远离支出。这些结论是得出的从小鼠敲除小鼠中观察到的变化以及用TBK1抑制剂弹药治疗的患者中观察到的。具体而言，TBK1的激活或诱导抑制AMPK活性，抑制脂质氧化和线粒体生物发生，同时增加脂肪生成。我们将以三个目的探讨这一假设：1）我们将评估肥胖期间TBK1激活和诱导的时间和空间方面，以及表征基本机制； 2）我们将探索禁食期间TBK1的激活和诱导并阐明分子机制； 3）我们将评估TBK1/AMPK轴控制中的作用肥胖期间的代谢和禁食，通过开发复合敲除鼠标模型，并评估该法规的时间和空间方面。这些发现可能揭示了能源消耗的在热量过剩和限制期间被压抑，并为这些毁灭性的新方法提供新的治疗方法疾病。