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：
10366269
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/10366269
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 Diurnal Rhythm Eating Equilibrium Exposure to Feedback Feeding behaviors Food Genes 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 Palate 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 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.

项目概要昼夜节律是行为和生理的自主循环，在现代社会中经常受到干扰。由于轮班工作的增加、夜间暴露于蓝光、睡眠中断以及消耗高浓度的可口的高脂肪饮食由驱动 24 小时睡眠的转录反馈环路编码。唤醒周期和激素水平、葡萄糖代谢和能量方面的生理节律。资助期间，我们揭示了大脑和外周时钟在节奏能量中的基本功能我们发现染色质构象的早晨/晚上变化。我们还发现，前脑和中脑神经元的时钟消融会损害细胞胰岛素的分泌。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）在我们的第一个例子中。目标是，我们将剖析驱动葡萄糖中重要的细胞功能的基因组节律的细胞和分子基础 (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。享乐和稳态喂养协调食欲驱动与葡萄糖稳态是我们的创新。工作是遗传学、基因组学和行为分析的多维整合，以获得分子洞察力最终，我们准备发现新的见解。研究中枢和外周时钟如何影响生理学，这些发现对治疗和预防肥胖和代谢综合征。