Integration of Feeding and Glucose Metabolism by the Circadian Gene Network

描述（由申请方提供）：来自公共卫生和临床流行病学研究的紧急数据为肥胖和2型糖尿病的新风险因素提供了令人信服的证据：在工作场所和家中引入长时间的觉醒，导致外部环境与协调进食、营养储存和能量消耗的内部综合生理系统之间的暂时中断。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性在人类基因水平上与葡萄糖稳态有关。在这种背景下，对摄食行为和葡萄糖代谢的长期临床和临床前研究也表明，摄食和葡萄糖周转的节律控制的扰动是代谢异常状态的标志;然而，昼夜节律中断，能量学和代谢之间的机械联系仍然不清楚。我们对昼夜节律中断对综合生理学影响的理解的重大突破源于过去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。虽然在20世纪90年代之前的昼夜节律研究的中心原则认为大脑主起搏器是哺乳动物计时的单一中心，但一个显着的发展是发现核心时钟基因包括几乎所有组织中每24小时振荡一次的转录-翻译反馈环，除了SCN。在2005年，我们报道了ENU衍生的Clock 19突变小鼠表现出对饮食诱导的肥胖、昼夜喂养模式改变、高血糖症以及令人惊讶的低胰岛素血症的易感性;然而，迄今为止，我们对时钟基因在喂养行为和综合生理学中的组织特异性作用的理解仍然不完整。在努力完善我们的知识的本地功能的时钟基因在两个大脑起搏器神经元，并在extra-SCN和外围位置，我们已经组装了一个独特的跨学科团队，现在提出结合联合收割机条件组织特异性基因靶向与广泛的平台，行为，生理和分子分析。基于我们令人兴奋的初步结果，其证明了脑或胰腺内时钟功能的条件性敲除的可行性，该提议的前瞻性目标将是确定脑内（Aim 1）或内分泌胰腺内（Aim 2）的时钟中断对在多组织昼夜节律突变体中观察到的肥胖和高血糖症的相对贡献。这项研究的结果将促进基因和行为交叉点的知识，并为干预肥胖和糖尿病提供新的治疗靶点和策略。

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.