Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism

项目总结/摘要 昼夜节律在几乎所有生物体的代谢平衡和营养利用中起着核心作用 和几乎所有的组织。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广泛的炎性 条件，其中它们的使用与突出的代谢副作用有关。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逆转这些 代谢异常的影响。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，类固醇给药频率，即每天与每周脉冲，促进 对瘦肉质量、运动耐力和能量产生显著相反的影响。与日常相反 剂量，每周糖皮质激素暴露改善营养吸收和代谢，促进肌肉生长 减少脂肪积累。具体来说，我已经发现，脉动糖皮质激素刺激支链 通过糖皮质激素受体反应的氨基酸氧化代谢和胰岛素敏感性 表观基因组计划专注于转录调节因子Kruppel样因子15（KLF 15）。此外，委员会认为， 脉冲糖皮质激素也激活BMAL 1及其分子级联。每个组件， 糖皮质激素受体、KLF 15和BMAL 1在其代谢作用中受昼夜节律振荡调节。 然而，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代谢重编程，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。为了解决这个问题，我建议（一）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，和（ii）调查表观基因组交叉调节 BMAL 1和KLF 15在驱动支链氨基酸代谢和能量产生中的作用。 实验将遵循从小鼠模型到人类细胞的基本转化路径， 方法包括表观遗传学、分子和代谢研究。本提案的总体目标是 为糖皮质激素和生物钟之间的交叉调节提供新的可操作知识， 对治疗肥胖和糖尿病等代谢性疾病的意义。

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.