Circadian Mechanisms of Hedonic Feeding in Obesity

肥胖症享乐喂养的昼夜节律机制

基本信息

批准号：
10455469
负责人：
Nathan James Waldeck
金额：
$ 4.2万
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455469
关键词：
ARNTL gene Ablation Address Affect Animals Architecture Area Behavior Behavioral Brain Brain region CRISPR/Cas technology Carbohydrates Cell Nucleus Cell Respiration Cells Chromatin Circadian Dysregulation Clinical Research Data Desire for food Diabetes Mellitus Disease Dopamine Dopaminergic Cell Eating Epigenetic Process Etiology Fatty acid glycerol esters Feedback Feeding behaviors Food Functional disorder Gene Expression Regulation Genes Genetic Genetic Models Genetic Transcription Genetic study Genomic approach High Fat Diet Homeostasis Human Hunger Hyperglycemia Hyperphagia Hypothalamic structure Impairment Industrialization Knock-out Lead Lighting Link Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Midbrain structure Modeling Molecular Motivation Mutant Strains Mice Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Palate Pathway interactions Peptides Periodicity Peripheral Phase Physiological Physiology Play Prevention Regulation Rewards Role Signal Transduction Sleep Sleep Deprivation Sleep Wake Cycle Sleep disturbances Synapses System Testing The Sun Therapeutic Time Tissues Transcriptional Regulation Variant Ventral Tegmental Area Weight Gain circadian circadian pacemaker circadian regulation comorbidity diet-induced obesity dopamine transporter dopaminergic neuron energy balance epidemiology study feeding gene network genetic approach glucose tolerance hedonic impaired glucose tolerance infancy insight molecular clock neuronal circuitry neuropeptide Y nodal myocyte novel obesity development open field behavior pandemic disease preference programs response shift work sleep pattern suprachiasmatic nucleus synaptogenesis transcriptome sequencing transcriptomics transmission process western diet

项目摘要

Project Summary The circadian clock is an auto-regulatory transcription feedback loop present in the brain and peripheral tissues that coordinates sleep/wake and physiology in anticipation of the rising of the sun each day. Epidemiologic, clinical and genetic studies have shown clock dysregulation contributes to both obesity and its metabolic co- morbidities. Recently, we have shown that abrogation of the core molecular clock component BMAL1 in hypothalamic hunger neurons leads to increased feeding at the wrong phase of the day/night cycle and causes impaired glucose tolerance, a hallmark of diabetes. AgRP neuron transcriptomics further identify circadian regulation of dopaminergic neurotransmitter synapse, indicating that clock disruption may lead to alterations in both the hedonic and homeostatic control of feeding. With a focus on understanding the mechanisms linking circadian systems to hedonic feeding, I have generated new data demonstrating that disruption of the molecular clock in dopaminergic neurons of the classical reward-promoting ventral tegmental area (VTA) results in hyperphagia of palatable high fat food and accelerates diet-induced obesity, hyperglycemia, impaired oxidative metabolism by respirometry, altered sleep patterns, and decreased daytime open field behavior. The scientific rationale underlying my present proposal is that the circadian clock modulates time-of-day dependent feeding and metabolic processes through the regulation of food-associated reward within midbrain dopaminergic neurons. This proposal seeks to contribute new insight into how neuronal clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of sleep-loss related disorders of obesity, metabolic syndrome, and type 2 diabetes mellitus.

项目概要生物钟是存在于大脑和周围组织中的自动调节转录反馈回路它协调睡眠/觉醒和生理机能，以预测每天太阳的升起。流行病学，临床和遗传学研究表明，生物钟失调会导致肥胖及其代谢综合征。发病率。最近，我们发现核心分子时钟组件 BMAL1 的废除下丘脑饥饿神经元导致在昼/夜周期的错误阶段进食增加，并导致糖耐量受损，糖尿病的一个标志。 AgRP 神经元转录组学进一步识别昼夜节律多巴胺能神经递质突触的调节，表明时钟中断可能导致喂养的享乐控制和稳态控制。重点是了解联系机制从昼夜节律系统到享乐喂养，我生成了新的数据，证明分子的破坏经典奖励促进腹侧被盖区（VTA）多巴胺能神经元的时钟导致过度食用可口的高脂肪食物并加速饮食引起的肥胖、高血糖、氧化受损通过呼吸测量法进行新陈代谢，改变睡眠模式，并减少白天的户外行为。科学的我目前建议的基本原理是生物钟调节一天中时间依赖性喂养通过调节中脑多巴胺能内与食物相关的奖励和代谢过程神经元。该提案旨在为神经元时钟如何同步行为和行为提供新的见解。转录节律影响生理学，对治疗和治疗具有广泛影响的发现预防与睡眠不足相关的肥胖症、代谢综合征和 2 型糖尿病。