Daily Rhythms and Health: Obesity and Related Disorders

描述（由申请人提供）：这项提案的目标是促进我发展成为一名独立的研究者和教育家，专注于阐明日常节律紊乱导致肥胖的机制。对啮齿类动物和人类的研究表明，肥胖个体的食物摄入时间会发生改变，但这种表型如何影响肥胖的病理生理机制尚不清楚。为了研究节律性代谢过程的调节以及它们在饮食引起的肥胖中是如何改变的，我开发了一个急性模型来监测喂食高脂肪饮食一周的小鼠的饮食行为和组织节律。我的初步研究表明，在摄入富含饱和脂肪的高脂肪饮食时，日常饮食行为的节奏会立即改变，肝脏生物钟的时间也会大大提前。提出的研究旨在阐明高脂肪饮食改变饮食行为和肝脏生理的机制。在本研究中，将利用进食行为的实时成像和肝脏生物发光节律的监测来验证富含饱和脂肪（而不是单一不饱和脂肪）的饮食通过toll样受体4介导的机制改变摄食行为和肝脏生理的日常节律的假设。为了实现本提案的目标，我将把我在昼夜节律生物学方面的经验与分析代谢生理学的新技术结合起来。我将从我的共同导师和指导委员会以及我之前的培训中汲取优势，培养一个独立的、新颖的研究方向。我的职业发展计划的关键要素包括代谢生理学的教学课程，沉浸在丰富的代谢和昼夜节律生物学研究的智力环境中，通过正式的研讨会、讲习班和与初级和高级科学家的互动获得职业发展技能。通过汇集优秀的指导团队，拥有最先进设备和设施的协同研究环境，以及职业成功方面的培训，这个职业发展奖将使我实现成为一名成功的独立科学家的长期职业目标，他的研究将广泛影响人类健康。

DESCRIPTION (provided by applicant): The goal of this proposal is to foster my development into an independent investigator and educator focused on elucidating the mechanisms by which disruption of daily rhythms contributes to obesity. Studies in rodents and humans have demonstrated that the timing of food intake is altered in obese individuals, but little is known about how this phenotype contributes to the pathophysiology of obesity. To investigate the tuning of rhythmic metabolic processes and how they are altered in diet-induced obesity, I developed an acute model to monitor eating behavior and tissue rhythms in mice fed high-fat diet for one week. My preliminary studies demonstrate that the daily rhythm of eating behavior is immediately altered and the timing of the circadian clock in the liver is robustly advanced during consumption of high-fat diet rich in saturated fat. The proposed studies aim to elucidate the mechanism whereby consumption of high-fat diet alters eating behavior and liver physiology. In this proposal, real-time imaging of eating behavior and monitoring of liver bioluminescence rhythms will be utilized to test the hypothesis that consumption of a diet rich in saturated fat (bt not monounsaturated fat) alters daily rhythms of feeding behavior and liver physiology through a toll-like receptor 4-mediated mechanism. To achieve the goals of this proposal, I will combine my experience in circadian biology with new techniques assaying metabolic physiology. I will draw from the strengths of my co-mentors and mentoring committee and from my prior training to cultivate an independent and novel line of research. Key elements of my career development plan include didactic coursework in metabolic physiology, immersion in an intellectual environment rich in the study of metabolism and circadian biology, and acquisition of career development skills through formal seminars, workshops, and interactions with junior and senior scientists. By bringing together a talented mentoring team, a synergistic research environment with state-of-the-art equipment and facilities, and training in career success, this career development award will allow me to achieve my long-term career goal of becoming a successful independent scientist whose research broadly impacts human health.