Integration of Feeding and Glucose Metabolism by the Circadian Gene Network

描述(申请人提供)：公共卫生和临床流行病学研究的紧急数据为肥胖和2型糖尿病的一个新的危险因素提供了令人信服的证据：在工作场所和家里引入长时间的清醒，导致外部环境和内部综合生理系统之间的暂时中断，协调进食、营养储存和能量消耗。在最近的大规模关联研究中，参与昼夜节律过程的关键基因的多态在人类基因水平上与血糖稳态有关。在这种背景下，一系列关于摄食行为和葡萄糖代谢的临床和临床前研究也表明，摄食和葡萄糖周转节奏控制的紊乱是代谢紊乱状态的特征；然而，昼夜节律紊乱、能量学和新陈代谢之间的机制联系仍然不清楚。在我们理解昼夜节律紊乱对综合生理学的影响方面的一个重大突破源于过去5年的发现，这些发现揭示了生物钟在控制体重和新陈代谢方面的核心作用。虽然20世纪90年代以前的昼夜节律研究的中心原则认为大脑主控起搏器是哺乳动物计时的单一中心，但一个显著的发展是发现核心时钟基因包括一个转录-翻译反馈环，在除SCN之外的几乎所有组织中每隔24小时振荡一次。2005年，我们报道了ENU来源的Clock 19突变小鼠表现出对饮食诱导的肥胖、昼夜进食模式改变、高血糖和令人惊讶的低血糖的易感性；然而，到目前为止，我们对Clock基因在进食行为和综合生理学中的组织特异性作用的了解仍然不完整。为了完善我们对时钟基因在大脑起搏神经元内以及在SCN外和周围位置的局部功能的了解，我们组建了一个独特的跨学科团队，现在建议将条件性组织特异性基因打靶与广泛的行为、生理和分子分析平台相结合。基于我们令人兴奋的初步结果，证明了大脑或胰腺内时钟功能的条件性敲除的可行性，这项建议的前瞻性目标将是确定大脑(目标1)或内分泌胰腺(目标2)的时钟中断对在多组织昼夜节律突变中观察到的肥胖和高血糖的相对贡献。这项拟议研究的结果将提高人们对基因和行为交叉点的认识，并为干预肥胖和糖尿病提供新的治疗目标和策略。 与公共卫生相关：肥胖和2型糖尿病代表着不断升级的公共卫生挑战，有可能侵蚀美国和发展中国家在医疗保健提供和可获得性方面的进展。我们的研究计划集中在一个令人兴奋的新发现上，即内部生物节律计时系统的破坏是肥胖和糖尿病的一个主要但鲜为人知的风险因素-为此，我们建议进行一系列实验研究，利用最先进的技术来解开内源性时钟系统在长期体重控制和葡萄糖耐量中的大脑和身体功能。最终，我们的研究将导致新的治疗策略，在公共卫生层面，从我们的工作中获得的洞察力将使行为改变能够改善新陈代谢健康。

DESCRIPTION (provided by applicant): Emergent data from public health and clinical epidemiological studies have provided convincing evidence for a new risk factor in obesity and type 2 diabetes mellitus: introduction of extended periods of wakefulness in the workplace and at home giving rise to temporal disruption between the external environment and internal integrative physiological systems coordinating feeding, nutrient storage and energy expenditure. In very recent large-scale association studies, polymorphisms in key genes involved in circadian processes have been implicated in glucose homeostasis at the genetic level in humans. Against this backdrop, a long-line of clinical and pre-clinical research into ingestive behavior and glucose metabolism has also shown that perturbations in the rhythmic control of both feeding and glucose turnover are hallmarks of dysmetabolic states; however the mechanistic links between circadian disruption, energetics and metabolism have remained obscure. A major breakthrough in our understanding of the impact of circadian disruption on integrative physiology originated in discoveries over the past 5 years that have uncovered a central role for the biological clock in the control of both body weight and metabolism. While the central tenet of circadian research prior to the 1990s held that the brain master pacemaker was the unitary center for mammalian timekeeping, a remarkable development has been the finding that core clock genes comprise a transcription-translation feedback loop oscillating every ~24 hrs in nearly all tissues in addition to the SCN. In 2005, we reported that ENU-derived Clock 19 mutant mice exhibit susceptibility to diet-induced obesity, altered day-night feeding patterns, hyperglycemia and, surprisingly, hypoinsulinemia; however, to date, our understanding of the tissue-specific roles of clock genes in feeding behavior and integrative physiology remains incomplete. In efforts to refine our knowledge of the local function of clock genes within both brain pacemaker neurons and in extra-SCN and peripheral locations, we have assembled a unique interdisciplinary team, and now propose to combine conditional tissue-specific gene targeting with an extensive platform for behavioral, physiological and molecular analyses. Based upon our exciting preliminary results which demonstrate feasibility of conditional knockout of clock function within either brain or pancreas, the forward-reaching goal of this proposal will be to determine the relative contribution of clock disruption within brain (Aim 1) or within endocrine pancreas (Aim 2) to the obesity and hyperglycemia observed in multi-tissue circadian mutants. Results from the proposed research will advance knowledge at the intersection of genes and behavior and provide new therapeutic targets and strategies to intervene in both obesity and diabetes mellitus. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes mellitus represent escalating public health challenges that threaten to erode advances in delivery and availability of healthcare throughout the US and the developing world. Our research proposal focuses on an exciting new discovery that disruption in the internal biological circadian timing system represents a major yet poorly understood risk factor in both obesity and diabetes-to this end, we propose a series of experimental studies using state-of-the-art technologies in order to unravel the brain and body functions of the endogenous clock system in both long-term weight control and glucose tolerance. Ultimately, our studies will lead to new therapeutic strategies and, at the public health level, insight gained from our work will enable behavioral modifications to improve metabolic health.