Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism

糖皮质激素和生物钟共同调节胰岛素敏感性和代谢

• 批准号: 9806667
• 负责人: Mattia Quattrocelli
• 金额: $ 14.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806667
• 关键词: ARNTL gene; Acetylation; Address; Adipocytes; Affect; Amino Acids; Automobile Driving; Award; Binding; Biological Assay; Branched-Chain Amino Acids; Cell Respiration; Cells; Chronic; Circadian Rhythms; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Diabetes Mellitus; Dose; Drug Prescriptions; Epigenetic Process; Exercise Tolerance; Fatty Acids; Fatty acid glycerol esters; Frequencies; Gene Deletion; Genetic; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glucose; Glucose Transporter; Goals; Growth; Hepatocyte; Homeostasis; Human; Hyperglycemia; Inflammatory; Insulin Resistance; Intake; Investigation; Knock-in; Knock-out; Knowledge; Light; Limb structure; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Myopathy; Nutrient; Obesity; Organism; Pathway interactions; Patients; Peripheral; Phase; Physiology; Play; Postdoctoral Fellow; Prednisone; Principal Investigator; Production; Publications; Publishing; Receptor Activation; Receptor Signaling; Regimen; Regulation; Research; Role; Signal Transduction; Specificity; Steroids; Testing; Therapeutic; Thinness; Tissues; Training; Transcription Coactivator; Triglycerides; Up-Regulation; Work; amino acid metabolism; base; blood glucose regulation; career; career development; cell type; chromatin immunoprecipitation; circadian; circadian pacemaker; circadian regulation; clinically significant; epigenomics; exercise capacity; experimental study; glucocorticoid receptor alpha; glucose disposal; improved; insulin sensitivity; interdisciplinary approach; metabolic abnormality assessment; molecular clock; mouse model; muscle aging; muscle metabolism; novel strategies; nutrient metabolism; pre-clinical; programs; response; side effect; stem; transcription factor; uptake; virtual

PROJECT SUMMARY/ABSTRACT Circadian rhythm plays a central role in metabolic homeostasis and nutrient utilization in nearly all organisms and virtually all tissues. Glucocorticoids are oscillatory regulators of metabolic function that act with cell and tissue-type specificity. Glucocorticoid steroids like prednisone are used to treat a wide range of inflammatory conditions, where their use is associated with prominent metabolic side effects. Chronic daily glucocorticoid intake promotes insulin resistance and obesity, and therefore novel approaches are needed to reverse these dysmetabolic effects. An important breakthrough in glucocorticoid-driven metabolic regulation stems from recently published discoveries that steroid dosing frequency, i.e. daily versus pulsatile weekly, promotes strikingly opposing effects on lean mass quality, exercise tolerance, and energy production. Contrary to daily dosing, weekly glucocorticoids exposure improves nutrient uptake and metabolism, boosting muscle growth and curtailing fat accrual. Specifically, I have uncovered that pulsatile glucocorticoids stimulate branched-chain amino acid oxidative metabolism and insulin sensitivity through a glucocorticoid receptor-responsive epigenomic program focusing on the transcriptional regulator Kruppel-like factor 15 (KLF15). Furthermore, pulsatile glucocorticoids also activate BMAL1 and its molecular cascades. Each of these components, the glucocorticoid receptor, KLF15 and BMAL1 are regulated by circadian oscillations in their metabolic effects. However, it is still unclear whether and how the circadian clock and glucocorticoid cascades interact to promote fuel utilization and favorable metabolic reprogramming, and whether environmental or genetic challenges to this interaction will affect metabolic physiology. To address this question, I propose to (i) dissect circadian regulation of glucocorticoid receptor activation and its effects on glucose and fatty acid utilization in metabolically active tissues like muscle, liver and fat, and (ii) investigate the epigenomic cross-regulation between BMAL1 and KLF15 in driving branched-chain amino acid metabolism and energy production. Experiments will follow a basic-to-translational path from mice models to human cells using a multidisciplinary approach encompassing epigenetic, molecular and metabolic studies. The overarching goal for this proposal is to provide new actionable knowledge of cross-regulation between glucocorticoids and circadian clock, with implications for the treatment of metabolic diseases like obesity and diabetes.

项目摘要/摘要 昼夜节律在几乎所有生物体的代谢稳态和营养利用中起着核心作用 几乎所有组织。糖皮质激素是代谢功能的振荡调节剂，可与细胞作用和 组织型特异性。糖皮质固醇（如泼尼松）用于治疗多种炎症 条件，它们的使用与显着的代谢副作用有关。慢性每日糖皮质激素 摄入促进胰岛素抵抗和肥胖，因此需要新的方法来扭转这些方法 非代谢效应。糖皮质激素驱动的代谢调节的重要突破来自 最近发表的发现类固醇给药频率，即每日与脉冲每周的发现，促进了 对精益质量质量，运动耐受性和能源产生的影响极大地相反。与每天相反 剂量，每周糖皮质激素暴露可改善养分的摄取和代谢，从而增强肌肉的生长 并减少脂肪应计。具体而言，我发现脉冲糖皮质激素会刺激分支链 氨基酸氧化代谢和胰岛素敏感性通过糖皮质激素受体反应性 表观基因组计划的重点是转录调节器Kruppel样因子15（KLF15）。此外， 脉冲糖皮质激素还激活BMAL1及其分子级联反应。这些组件中的每一个， 糖皮质激素受体，KLF15和BMAL1受昼夜节律的代谢作用调节。 但是，尚不清楚昼夜节律时钟和糖皮质激素级联反应是如何相互作用的 促进燃料利用和有利的代谢重编程，以及环境还是遗传 这种相互作用的挑战将影响代谢生理。为了解决这个问题，我建议（i）剖析 昼夜节律调节糖皮质激素受体激活及其对葡萄糖和脂肪酸利用的影响 代谢活性组织，例如肌肉，肝脏和脂肪，以及（ii）研究表观基因组交叉调节 在驱动分支链氨基酸的代谢和能量产生的BMAL1和KLF15之间。 实验将遵循从小鼠模型到人类细胞的基本转换路径，使用多学科 方法包括表观遗传学，分子和代谢研究。该提议的总体目标是 为了提供新的可操作知识，了解糖皮质激素和昼夜节律之间的交叉调节 对治疗肥胖和糖尿病等代谢疾病的影响。