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

项目摘要 昼夜节律是行为和生理的自主周期，在现代生活中经历常规中断。 社会由于轮班工作的增加，晚上暴露在蓝光下，睡眠中断，以及高- 可口的高脂肪饮食分子钟由转录反馈回路编码，驱动24小时睡眠- 唤醒周期和激素水平、葡萄糖代谢和能量学的生理节律。上一 格兰特期间，我们揭示了大脑和周边时钟的节奏能量的基本功能 体内平衡和葡萄糖代谢。我们发现染色质构象的早晚变化 控制胰岛细胞胰岛素分泌。我们还发现，在前脑和中脑神经元的时钟消融损害 食欲驱动，睡眠/觉醒节律，能量平衡，葡萄糖耐量和转录，尽管存在差距 仍然是我们对行为和新陈代谢的节律整合机制的理解。 在这里，我们试图扩大我们的洞察力昼夜节律机制联系行为和新陈代谢。(i)在我们的第一 我们将剖析基因组节律的细胞和分子基础，这种基因组节律在葡萄糖代谢中起重要作用。 在整个睡眠-觉醒周期中的稳定性。(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 快乐和自我平衡的进食协调食欲驱动与葡萄糖的自我平衡。我们的创新 这项工作是遗传学、基因组学和行为分析的多维整合，以获得分子洞察力 有节奏的神经细胞功能和神经元对饥饿的控制。最终，我们将发现新的见解 研究中枢和外周时钟如何影响生理学，这些发现对神经科学有着广泛的影响。 治疗和预防肥胖和代谢综合征。

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.