Cross-regulation of Immunometabolism and Circadian Pathways in Obesity Pathophysiology

肥胖病理生理学中免疫代谢和昼夜节律途径的交叉调节

• 批准号: 10597527
• 负责人: Joseph Bass
• 金额: $ 48.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597527
• 关键词: ARNTL gene; Adipocytes; Adipose tissue; Animals; Binge Eating; Biological Assay; Cardiovascular Diseases; Cells; Chromatin; Circadian Dysregulation; Circadian Rhythms; Citric Acid Cycle; Coupled; Darkness; Data; Deposition; Diabetes Mellitus; Disease; Eating; Enzymes; Epigenetic Process; Expression Profiling; Fasting; Fatty acid glycerol esters; Feeding behaviors; Fibrosis; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Glucose; Health; High Fat Diet; Impairment; Individual; Inflammation; Inflammatory; Jet Lag Syndrome; Knockout Mice; Label; Light; Lipids; Liver; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Nutrient; Obesity; Obesity Epidemic; Overnutrition; Pathway interactions; Periodicity; Process; Public Health; Regulation; Respiration; Role; Shift-Work Sleep Disorder; Site; Skeletal Muscle; Sleep; Stress; Succinates; System; Testing; Time; Time-restricted feeding; Tracer; Transgenic Model; Transposase; Tricarboxylic Acids; Visceral; blood glucose regulation; cell type; circadian; circadian pacemaker; cohort; combat; comparison group; energy balance; feeding; insulin sensitivity; lipid biosynthesis; metabolic phenotype; novel; organic acid; overexpression; preservation; programs; respiratory; shift work; social; transcriptomics

Project Summary Obesity and diabetes are increased among individuals subjected to shiftwork, reduced sleep, and social jetlag. High fat diet (HFD) misaligns intrinsic circadian cycles with the light/dark cycle and alters oscillations of metabolic genes in visceral adipose tissue, a key site in the control of energy balance, glucose regulation, and inflammatory disorders. Conversely, restricting HFD to the dark period only realigns meal time with circadian rhythms and enhances insulin sensitivity, promoting healthful obesity. How circadian disruption in visceral adipose tissue contributes to obesity pathophysiology remains unknown. In exciting new data, we show strong day/night rhythms in adipocyte mitochondrial respiration with maximal uncoupling at the onset of the active period that is dependent upon a functional clock. Further, 13C-glucose entry into the tricarboxylic acid (TCA) cycle is also highest at the beginning of the active period, indicating autonomous circadian control of WAT metabolic flux across the day/night cycle. Surprisingly, in Bmal1-/- adipocytes, we observe reprogramming of adipocyte metabolism with increased 13C labeling in succinate and reduced levels of other TCA intermediates, a signature of stress and ROS accumulation. Here we seek to test the hypothesis that the circadian clock controls energy flux within visceral adipose tissue at the level of fuel entry into the TCA cycle through a process disrupted by HFD. In Aim 1, we will test the hypothesis that circadian coordination of feeding time and adipose energy utilization cycles promote healthful adipose expansion using genetic lineage tracer animals and metabolic phenotyping. We will assess adipose tissue remodeling and 13C glucose flux into the TCA cycle in addition to lipid and organic acids across the light-dark cycle in mice fed regular chow or HFD either ad lib or time-restricted to the light (misttimed feeding) or dark (optimal time feeding) period at thermoneutrality (30oC). We will also test the requirement of the WAT clock and the effect of adipose-specific BMAL1 overexpression in HFD on adipose remodeling, inflammation, fibrosis, and glucose homeostasis. Aim 1 results will establish the interplay between the WAT clock and feeding time in energy flux, metabolic health, and capacity for healthful adipose expansion, particularly with the new addition of the light-only feeding group for comparison to the dark- only and AL cohorts. In Aim 2, we will test the hypothesis that HFD abrogates circadian energetic cycles in visceral adipose tissue and induces epigenetic remodeling towards a proinflammatory cell fate. We will perform tandem chromatin and expression profiling in adipocytes to identify the time signature and molecular drivers of visceral WAT remodeling in ad lib and light- and dark-only-fed mice on HFD. Finally, we will examine whether BMAL1 overexpression during HFD preserves the healthful chromatin landscape of regular chow fed mice. Results of Aim 2 will determine how clock control of chromatin activity and transcription contributes to healthful obesity. Collectively, these studies will define the role of time-of-day in adipogenesis and nutrient flux, uncovering novel targets to combat the immunometabolic complications of obesity and circadian disruption.

项目概要 轮班工作、睡眠不足和社交时差的个体肥胖和糖尿病的发病率会增加。 高脂肪饮食 (HFD) 使内在昼夜节律周期与光/暗周期错位，并改变新陈代谢的波动 内脏脂肪组织中的基因是控制能量平衡、葡萄糖调节和炎症的关键部位 失调。相反，将 HFD 限制在黑暗时期只会使进餐时间与昼夜节律重新调整， 增强胰岛素敏感性，促进健康肥胖。内脏脂肪组织的昼夜节律如何受到干扰 导致肥胖的病理生理学仍然未知。在令人兴奋的新数据中，我们表现出强劲的白天/夜晚 脂肪细胞线粒体呼吸的节律在活跃期开始时最大解偶联，即 依赖于功能时钟。此外，13C-葡萄糖进入三羧酸（TCA）循环也 在活跃期开始时最高，表明 WAT 代谢通量的自主昼夜节律控制 跨越昼夜循环。令人惊讶的是，在 Bmal1-/- 脂肪细胞中，我们观察到脂肪细胞的重编程 琥珀酸中 13C 标记增加和其他 TCA 中间体水平降低的代谢，这是一个标志 应激和ROS积累。在这里，我们试图检验生物钟控制的假设 通过一个过程进入 TCA 循环的燃料水平上内脏脂肪组织内的能量通量 受到 HFD 的干扰。在目标 1 中，我们将检验以下假设：进食时间和脂肪的昼夜节律协调 能量利用循环利用遗传谱系示踪动物和代谢促进健康的脂肪扩张 表型分析。除了以下之外，我们还将评估脂肪组织重塑和进入 TCA 循环的 13C 葡萄糖通量 随意或限时喂养普通食物或 HFD 的小鼠的光暗循环中的脂质和有机酸 到热中性 (30oC) 下的光照（不定时喂食）或黑暗（最佳时间喂食）时期。我们也会测试 WAT 时钟的要求以及 HFD 中脂肪特异性 BMAL1 过表达对脂肪的影响 重塑、炎症、纤维化和葡萄糖稳态。目标 1 结果将建立相互作用 WAT 时钟和进食时间之间的能量通量、代谢健康状况和健康能力 脂肪膨胀，特别是新添加的仅光喂养组与黑暗喂养组进行比较 仅和 AL 队列。在目标 2 中，我们将检验 HFD 消除昼夜节律能量循环的假设 内脏脂肪组织并诱导表观遗传重塑以实现促炎细胞的命运。我们将表演 脂肪细胞中的串联染色质和表达谱，以确定脂肪细胞的时间特征和分子驱动因素 HFD 中自由活动以及仅光和暗喂养的小鼠的内脏 WAT 重塑。最后，我们将检查是否 HFD 期间 BMAL1 过度表达保留了常规食物喂养小鼠的健康染色质景观。 目标 2 的结果将确定染色质活性和转录的时钟控制如何促进 健康的肥胖。总的来说，这些研究将定义一天中的时间在脂肪生成和营养流动中的作用， 发现新的靶点来对抗肥胖和昼夜节律紊乱引起的免疫代谢并发症。