The Physiological Relevance of SIRT1 in Brain on Energy and Glucose Homeostasis

描述(申请人提供)：肥胖和2型糖尿病(2 DM)影响着数百万人，是美国主要健康问题的原因。这两种情况都有一系列危及生命的并发症，包括心血管疾病。尽管进行了密集的研究，但导致肥胖和/或2型糖尿病的主要缺陷在很大程度上仍然未知。为了预防和开发针对这些病理的更有效的治疗方法，需要更好地了解身体能量和葡萄糖动态平衡的基本生理学、神经内分泌学和行为。下丘脑和代谢感受器蛋白在能量和葡萄糖平衡中起着重要作用。在这里，通过使用神经元特异性的Cre/loxP介导的操作，将产生独特的动物模型，在该模型中，SIRT1(一种代谢感受器蛋白)要么在受限的下丘脑神经元中过度表达，要么被删除。这些小鼠将接受几项表型测试，以确定下丘脑神经元中的SIRT1是否是正常体重和血糖稳态所必需的。这些研究的结果有望增加我们对能量和葡萄糖稳态协调控制的分子机制和神经回路的理解。公共卫生相关性：肥胖和2型糖尿病影响着数百万人，是美国主要健康问题的原因。为了预防和开发针对这些疾病的更有效的治疗方法，需要更好地了解身体能量和葡萄糖动态平衡的基本机制。这里提出的这项研究旨在确定这些共同控制体重和葡萄糖平衡的机制(蛋白质和神经元)。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (2DM) affect millions of people and are the cause of major health problems in the United States. Both conditions have a long array of life threatening complications, including cardiovascular diseases. Despite intense research, the primary defects causing obesity and/or 2DM are still largely unknown. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic physiology, neuroendocrinology and behavior of body energy and glucose homeostasis is needed. The hypothalamus and metabolic-sensor proteins exert important functions on energy and glucose balance. Here, by employing neuron-specific, Cre/loxP-mediated manipulations, unique animal models in which SIRT1 (a metabolic-sensor protein) is either overexpressed or deleted only in restricted hypothalamic neurons will be generated. These mice will be subjected to several phenotypic tests to determine whether SIRT1 in hypothalamic neurons is required for normal body weight and glucose homeostasis. Results from these studies are expected to increase our understanding of the molecular mechanisms and neurocircuits that underlie coordinated control of energy and glucose homeostasis. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes affect millions of people and are the cause of major health problems in the United States. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic mechanisms of body energy and glucose homeostasis is needed. The study proposed here is aimed at identifying these mechanisms (proteins and neurons) that in concert govern body weight and glucose balance.