Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network

项目总结 昼夜节律是行为和生理的自主循环，在现代社会中经历常规的破坏 社会上由于轮班工作的增加，夜间暴露在蓝光下，睡眠中断，以及高消费- 可口的高脂肪饮食。分子时钟由转录反馈环路编码，驱动24小时睡眠- 唤醒周期和荷尔蒙水平、葡萄糖代谢和能量的生理节律。在上一次 格兰特时期，我们揭示了大脑和外周时钟在节律性能量中的基本功能 动态平衡和葡萄糖代谢。我们发现染色质构象的早晚变化 控制细胞的胰岛素分泌。我们还发现，前脑和中脑神经元的时钟消融会造成损害。 食欲驱动、睡眠/清醒节律、能量平衡、葡萄糖耐量和转录，尽管有差距 仍然是我们对行为和新陈代谢有节奏地整合的机制的理解。 在这里，我们试图扩展我们对连接行为和新陈代谢的昼夜节律机制的洞察。(I)在我们的第一次 目的：我们将剖析驱动的基因组节律的细胞和分子基础--葡萄糖中重要的细胞功能 在睡眠-觉醒周期中保持恒定。(Ii)在我们的第二个目标中，我们将确定节律的神经回路基础 享乐式和动态式喂养将食欲驱动与葡萄糖动态平衡相协调。我们的一项创新 工作是遗传学、基因组学和行为分析的多维整合，以获得分子洞察力 转化为有节奏的细胞功能和神经元对饥饿的控制。最终，我们准备发现新的洞察力 关于中枢和外周时钟如何影响生理学，这些发现对 肥胖症和代谢综合征的治疗和预防。

PROJECT SUMMARY Circadian rhythms are autonomous cycles of behavior and physiology that undergo routine disruption in modern society due to the rise in shift work, exposure to blue light at night, disrupted sleep, and consumption of highly- palatable high-fat diet. Molecular clocks are encoded by transcription feedback loops that drive the 24-hr sleep- wake cycle and physiological rhythms in hormone levels, glucose metabolism, and energetics. In the previous grant period, we revealed an essential function for both brain and peripheral clocks in rhythmic energy homeostasis and glucose metabolism. We showed that morning/evening variation in chromatin conformation controls -cell insulin secretion. We also showed that clock ablation in neurons of forebrain and midbrain impairs appetitive drive, sleep/wake rhythms, energy balance, glucose tolerance, and transcription, although a gap remains in our understanding of the mechanisms underlying rhythmic integration of behavior and metabolism. Here we seek to extend our insight into circadian mechanisms linking behavior and metabolism. (i) In our first aim, we will dissect the cell and molecular basis for genomic rhythms driving -cell function important in glucose constancy across the sleep-wake cycle. (ii) In our second aim, we will identify the neurocircuit basis for rhythms of hedonic and homeostatic feeding coordinating appetitive drive with glucose homeostasis. An innovation of our work is the multidimensional integration of genetics, genomics, and behavioral analyses to gain molecular insight into rhythmic -cell function and neuronal control of hunger. Ultimately, we are poised to uncover new insight into how central and peripheral clocks impact physiology, findings which have broad implications for the treatment and prevention of obesity and metabolic syndrome.