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: 10390430
• 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/10390430
• 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; 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; base; 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; 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.

项目摘要 受到转移工作，睡眠减少和社交喷气lag的个体中的肥胖和糖尿病增加。 高脂肪饮食（HFD）错过了固有的昼夜节律，其光/黑暗周期和改变了代谢的振荡 内脏脂肪组织中的基因，能量平衡，葡萄糖调节和炎症的关键部位 疾病。相反，将HFD限制到黑暗时期，只能通过昼夜节律和 增强胰岛素敏感性，促进健康的肥胖症。内脏脂肪组织中的昼夜节律如何破坏 有助于肥胖病理生理学的原因仍然未知。在令人兴奋的新数据中，我们显示了强大的白天/夜晚 脂肪细胞线粒体呼吸中的节奏在活动期开始时具有最大解偶联 取决于功能时钟。此外，进入三羧酸（TCA）周期的13C-葡萄糖也是 在活动期开始时最高，表明自治的昼夜节律控制WAT代谢通量 整天/夜间周期。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 新陈代谢增加了琥珀酸酯中13C标记和其他TCA中间体水平降低，这是一个特征 压力和ROS积累。在这里，我们试图检验昼夜节律控制的假设 在燃料进入TCA周期的内脏脂肪组织内的能量通量通过一个过程 被HFD破坏。在AIM 1中，我们将检验以下假设 能源利用周期使用遗传谱系示踪动物和代谢促进健康的脂肪扩张 表型。我们还将评估脂肪组织的重塑和13C葡萄糖通量，除了 在饲喂常规食物或HFD的小鼠中，脂质和有机酸遍布脂肪循环或限制时间限制 在热反态（30oC）处的光线（雾化进料）或黑暗（最佳时间喂养）期。我们还将测试 WAT时钟的需求以及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。 AIM 1结果将建立相互作用 在能量通量，代谢健康和健康能力的饮水时钟和喂养时间之间 脂肪膨胀，尤其是新添加的仅轻度喂养组，以与深色 唯一的和al群体。在AIM 2中，我们将测试HFD废除昼夜节律循环的假设 内脏脂肪组织并诱导表观遗传重塑朝向促炎细胞命运。我们将表演 脂肪细胞中的串联染色质和表达分析，以识别时间签名和分子驱动因素 HFD上的Ad Lib，轻且仅喂养的小鼠进行内脏WAT重塑。最后，我们将研究是否 HFD期间的BMAL1过表达保留了常规食小鼠的健康染色质景观。 AIM 2的结果将决定时钟的染色质活性和转录的控制如何有助于 健康的肥胖。总的来说，这些研究将定义当天在脂肪形成和营养通量中的作用， 揭示新的靶标，以应对肥胖和昼夜节律破坏的免疫代谢并发症。