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: 10191173
• 负责人: Mattia Quattrocelli
• 金额: $ 14.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 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/10191173
• 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; Wild Type Mouse; 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.

项目概要/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发挥着核心作用 和几乎所有组织。糖皮质激素是代谢功能的振荡调节剂，与细胞和 组织类型特异性。糖皮质激素类固醇如泼尼松用于治疗多种炎症 条件下，其使用与显着的代谢副作用相关。慢性每日糖皮质激素 摄入量会促进胰岛素抵抗和肥胖，因此需要新的方法来扭转这些 代谢障碍的影响。糖皮质激素驱动的代谢调节的一个重要突破源于 最近发表的发现表明，类固醇给药频率（即每天与每周脉冲式）可促进 对瘦体重、运动耐量和能量产生具有显着相反的影响。与日常相反 每周服用糖皮质激素可改善营养吸收和新陈代谢，促进肌肉生长 并减少脂肪累积。具体来说，我发现脉动糖皮质激素会刺激支链 通过糖皮质激素受体反应调节氨基酸氧化代谢和胰岛素敏感性 表观基因组计划重点关注转录调节因子 Kruppel 样因子 15 (KLF15)。此外， 脉冲性糖皮质激素也会激活 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 的代谢效应受昼夜节律振荡调节。 然而，目前尚不清楚生物钟和糖皮质激素级联是否以及如何相互作用 促进燃料利用和有利的代谢重编程，无论是环境的还是遗传的 这种相互作用的挑战将影响代谢生理学。为了解决这个问题，我建议（i）剖析 糖皮质激素受体激活的昼夜节律调节及其对葡萄糖和脂肪酸利用的影响 代谢活跃的组织，如肌肉、肝脏和脂肪，以及 (ii) 研究表观基因组交叉调节 BMAL1 和 KLF15 在驱动支链氨基酸代谢和能量产生方面的作用。 实验将采用多学科的方法，遵循从小鼠模型到人类细胞的基本转化路径 方法涵盖表观遗传学、分子和代谢研究。该提案的总体目标是 提供糖皮质激素和生物钟之间交叉调节的新的可操作知识， 对治疗肥胖和糖尿病等代谢疾病的影响。