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

昼夜节律基因网络整合进食时间和葡萄糖代谢

基本信息

批准号：
10668512
负责人：
Joseph Bass
金额：
$ 48.65万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668512
关键词：
Ablation Automobile Driving B-Lymphocytes Behavior Behavioral Beta Cell Brain Carbohydrates Cell physiology Cells Chromatin Circadian Rhythms Consumption Cyclic AMP Response Element Desire for food Diabetes Mellitus Dimensions Diurnal Rhythm Eating Equilibrium Exposure to Feedback Feeding behaviors Food Genetic Genetic Transcription Genomics Glucose Goals Grant Health High Fat Diet Homeostasis Hormones Human Hunger Hyperphagia Hypothalamic structure Impairment Insulin Light Link Metabolic syndrome Metabolism Midbrain structure Modernization Molecular Molecular Conformation Motivation Mus Neurons Obesity Obesity Epidemic Periodicity Peripheral Physiological Physiology Prosencephalon Public Health RNA Processing Regulation Rewards Role Site Sleep Sleep Wake Cycle Sleep disturbances Societies Testing Time Variant Ventral Tegmental Area Work blood glucose regulation circadian circadian pacemaker circadian regulation dopaminergic neuron energy balance feeding gene network glucose metabolism glucose tolerance hedonic impaired glucose tolerance innovation insight insulin secretion islet molecular clock obesity prevention shift work three dimensional structure transcription factor transcriptomics

项目摘要

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.

项目摘要昼夜节律是行为和生理的自主周期，在现代中受到常规破坏社会由于转移工作的增加，夜间暴露于蓝光，睡眠中断以及高度消费可口的高脂饮食。分子时钟由驱动24小时睡眠的转录反馈回路编码骑马水平，葡萄糖代谢和能量学的唤醒周期和物理节奏。在上一个赠款期，我们揭示了节奏能量中大脑和外围钟的重要功能稳态和葡萄糖代谢。我们展示了染色质构象的早晨/晚上变化控制细胞胰岛素分泌。我们还表明，前脑和中脑损伤的神经元中的时钟消融开胃驱动，睡眠/唤醒节奏，能量平衡，葡萄糖耐受性和转录，尽管差距是仍然是我们对行为和代谢有节奏融合的机制的理解。在这里，我们试图扩展对关联行为和新陈代谢的昼夜节律机制的洞察力。（i）在我们的第一个目的，我们将剖析驱动基因组节律的细胞和分子基础。在整个睡眠循环中的恒定。（ii）在我们的第二个目标中，我们将确定节奏的神经电路基础与葡萄糖稳态的享乐主义和体内平衡喂养协调驱动器。我们的创新工作是遗传学，基因组学和行为分析的多维整合以获得分子洞察力进入节奏细胞功能和饥饿的神经元控制。最终，我们被毒死了，以发现新的洞察力进入中心时钟和外围时钟如何影响生理学，发现对治疗和预防肥胖和代谢综合征。