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

描述（由申请人提供）：肥胖和2型糖尿病（2DM）影响着数百万人，是美国主要健康问题的原因。这两种疾病都有一系列危及生命的并发症，包括心血管疾病。尽管有大量的研究，但导致肥胖和/或2型糖尿病的主要缺陷在很大程度上仍是未知的。为了预防和开发更有效的治疗这些疾病，需要更好地了解基本生理学，神经内分泌学和身体能量和葡萄糖稳态的行为。下丘脑和代谢敏感蛋白在能量和葡萄糖平衡中发挥重要作用。在这里，通过采用神经元特异性，Cre/ loxp介导的操作，将产生独特的动物模型，其中SIRT1（一种代谢传感器蛋白）仅在受限的下丘脑神经元中过表达或缺失。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是否是正常体重和葡萄糖稳态所必需的。这些研究的结果有望增加我们对分子机制和神经回路的理解，这些机制和神经回路是协调控制能量和葡萄糖稳态的基础。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。为了预防和开发更有效的治疗这些疾病，需要更好地了解身体能量和葡萄糖稳态的基本机制。本文提出的研究旨在确定协同控制体重和葡萄糖平衡的这些机制（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.