Integration of Feeding and Glucose Metabolism by the Circadian Gene Network

描述（由申请人提供）：来自公共卫生和临床流行病学研究的新数据为肥胖和2型糖尿病的一个新的危险因素提供了令人信服的证据：在工作场所和家中引入长时间的清醒，导致外部环境和协调喂养，营养储存和能量消耗的内部综合生理系统之间的时间中断。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遗传水平上与人类葡萄糖稳态有关。在此背景下，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，摄食和葡萄糖转换节律控制的紊乱是代谢不良状态的标志；然而，昼夜节律中断、能量学和新陈代谢之间的机制联系仍然不清楚。我们对昼夜节律中断对综合生理学影响的理解取得了重大突破，这源于过去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年代之前的昼夜节律研究的核心原则认为，大脑的主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-翻译反馈回路，除SCN外，几乎所有组织中每24小时振荡一次。2005年，我们报道了enu衍生的Clock 19突变小鼠表现出对饮食引起的肥胖、昼夜喂养模式改变、高血糖和令人惊讶的低胰岛素血症的易感；然而，到目前为止，我们对生物钟基因在摄食行为和综合生理中的组织特异性作用的理解仍然不完整。为了完善我们对大脑起搏器神经元、scn外区和外周位置时钟基因局部功能的了解，我们组建了一个独特的跨学科团队，现在建议将条件组织特异性基因靶向与广泛的行为、生理和分子分析平台结合起来。基于我们激动人心的初步结果，证明了在大脑或胰腺中有条件地敲除时钟功能的可行性，本提案的前瞻性目标将是确定大脑（目标1）或内分泌胰腺（目标2）中的时钟中断对多组织昼夜节律突变体中观察到的肥胖和高血糖的相对贡献。本研究的结果将促进基因和行为交叉领域的研究，并为肥胖和糖尿病的干预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.