Integrative Metabolic Adaptations to Enviromental and Nutritional Challenge

描述(申请人提供：糖尿病是一种多器官疾病，对复杂的遗传和环境因素做出反应。全面了解胰岛素抵抗和2型糖尿病(T2 DM)需要一种综合的方法，即在机体外应激包括营养过剩和正常昼夜节律中断的情况下，不同类型的细胞如何通过激素、神经和代谢信号相互影响。本申请中提出的所有研究的一个目标是从分子角度解释正常和病理代谢，强调细胞自主过程以及那些依赖于生物整合的过程。该计划项目汇集了五名杰出的研究人员，每个人都作为一名独立的研究人员在过去取得了相当大的成功，但每个人都对科学合作的价值抱有真正的信念。每个PI专注于一个特定的器官系统，以及它如何与其他组织和外部压力相互作用，并与研究相关问题的其他PI密切沟通。在项目1中，Lazar阐述了抵抗素如何协调多器官对营养过载的反应，在这种反应中，炎症反应会导致胰岛素靶组织和心血管系统的不良后果。在项目2中，Stoffers关注的是β细胞对外周压力的反应 胰岛素抵抗，测试了一个有趣的模型，该模型将转录调节与内质网生物合成和细胞生长联系起来。在项目3中，Ahima使用了一个模拟人类昼夜节律紊乱的小鼠喂食夹带模型来研究中枢神经系统如何影响肝脏新陈代谢。在项目4中，凯斯特纳还研究了在荷尔蒙环境如何影响肝脏葡萄糖代谢的转录控制的背景下，对扰乱的中枢时钟的反应。最后，在项目5中，Birnbaum还研究了肝脏代谢如何应对肥胖的压力，但也询问了抗糖尿病药物二甲双胍是如何使其正常化的。这些项目得到了三个核心的支持，这三个核心提供组织化学分析、转基因小鼠的生成及其代谢表型。

DESCRIPTION (provided by applicant: Diabetes is a disease of multiple organs responding to complex genetic and environmental factors. A complete understanding of insulin resistance and type 2 diabetes mellitus (T2DM) requires an integrative approach that asks how different cell types influence each other through hormonal, neural, and metabolic signals all in the context of extra-organismal stresses including overnutrition and disruptions in normal circadian rhythms. A goal of all studies proposed in this application is to explain normal and pathological metabolism in molecular terms, emphasizing both cell autonomous processes as well as those that depend on organismal integration. The Program Project brings together five outstanding investigators, each with considerable past success as an independent investigator, but each also with a genuine belief in the value of scientific collaboration. Each PI focuses on a specific organ system and how it interacts with other tissues and external stresses, and works in close communication other PIs who study related problems. In Project 1, Lazar addresses how resistin coordinates the multi-organ response to nutritional overload, in which an inflammatory response leads to adverse consequences in insulin target tissues and the cardiovascular system. In Project 2, Stoffers focuses on the response of the beta cell to the stress of peripheral insulin resistance, testing an intriguing model that connects transcriptional regulation to endoplasmic reticulum biosynthesis and cell growth. In Project 3, Ahima uses a mouse feeding entrainment model that mimics circadian disruption in humans to examine how the central nervous system influences hepatic metabolism. In Project 4, Kaestner also studies the response to a perturbed central clock, but in the context of how the hormonal milieu influences the transcriptional control of liver glucose metabolism. Lastly, in Project 5, Birnbaum also considers how hepatic metabolism responds to the stress of obesity, but also asks how it is normalized by the antidiabetic drug metformin. The projects are supported by three Cores that provide histochemical analysis, generation of genetically modified mice, and their metabolic phenotyping.