Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism

项目摘要/摘要 昼夜节律在几乎所有生物体的代谢动态平衡和养分利用中起着核心作用 以及几乎所有的纸巾。糖皮质激素是代谢功能的振荡调节器，与细胞和 组织类型特异性。糖皮质激素如泼尼松可用于治疗多种炎症性疾病 在条件下，它们的使用与显著的代谢副作用有关。慢性每日糖皮质激素 摄入会促进胰岛素抵抗和肥胖，因此需要新的方法来逆转这些 代谢障碍。糖皮质激素驱动的代谢调节的一个重要突破源于 最近发表的研究发现，类固醇剂量的频率，即每天与每周脉动，促进 对瘦身质量、运动耐量和能量产生的影响截然相反。与每日相反 剂量，每周接触糖皮质激素改善营养吸收和新陈代谢，促进肌肉生长 并减少脂肪的积累。具体地说，我发现脉冲性糖皮质激素刺激支链 糖皮质激素受体反应性氨基酸氧化代谢与胰岛素敏感性 表观基因组计划，重点是转录调控因子Kruppel样因子15(KLF15)。此外， 搏动性糖皮质激素也激活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的代谢作用受昼夜波动的调节。 然而，目前仍不清楚生物钟和糖皮质激素级联反应是否以及如何相互作用。 促进燃料利用和有利的新陈代谢重新编程，无论是环境还是遗传 对这种相互作用的挑战将影响代谢生理学。为了回答这个问题，我建议(I)剖析 糖皮质激素受体激活的昼夜节律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)研究表观基因组的交叉调节 BMAL1和KLF15之间在驱动支链氨基酸代谢和能量产生方面的作用。 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。这项提案的首要目标是 提供糖皮质激素和生物钟之间交叉调节的新的可操作的知识， 这对肥胖和糖尿病等代谢性疾病的治疗具有重要意义。

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.