SH2-B regulation of body weight and energy homostasis

SH2-B 调节体重和能量稳态

• 批准号: 7149367
• 负责人: LIANGYOU RUI
• 金额: $ 29.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149367
• 关键词: JAK kinase; basal metabolism; bioenergetics; body weight; enzyme activity; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hormone sensitivity /resistance; hypothalamus; laboratory mouse; leptin; obesity; protein protein interaction; receptor binding; thermogenesis; transport proteins

DESCRIPTION (provided by applicant): The long-term goal of this research program is to elucidate molecular mechanisms of obesity and obesity- associated metabolic diseases. Obesity is a major risk factor for hypertension, atherosclerosis, stroke, heart attack, type 2 diabetes and cancer, which reduces both lifespan and life quality. Healthcare costs for obesity and obesity-associated diseases are huge and continue to rise rapidly. Recent identification of the adipose hormone leptin has transformed our understanding of the regulation of body weight and energy homeostasis. Leptin, which is produced by adipose tissue and secreted into the bloodstream in proportion to the total fat mass, binds to and activates its receptor in the hypothalamus, relaying peripheral nutritional signals to the central nervous system. Impaired leptin responses (leptin resistance) lead to overweight and obesity. Leptin resistance is mainly caused by the inhibition of cell signaling downstream of the leptin receptor (LEPRb). LEPRb binds to and activates JAK2, a cytoplasmic tyrosine kinase that mediates key signaling pathways in response to leptin. We recently identified SH2-B, an SH2 and PH domain-containing adaptor protein, as a JAK2-interacting protein in cells. We hypothesize that SH2-B is a key enhancer of leptin regulation of body weight and energy homeostasis, and defects in SH2-B expression and action may be an important risk factor for leptin resistance and obesity. To test this hypothesis, we disrupted the SH2-B gene in mice. We demonstrate that SH2-B knockout mice are severely leptin resistant and obese. In this proposal, we shall extend our preliminary work and firmly establish the essential role of SH2-B in the control of body weight and energy homeostasis. We shall elucidate the molecular mechanisms of SH2-B action using biochemical, genetic and physiological approaches. The findings from this project will provide a scientific basis for design of new therapeutic treatments for obesity and obesity-associated metabolic diseases by targeting SH2-B expression and action. Specific Aims are: 1. Determine whether SH2-B regulates energy metabolism and body weight by directly enhancing leptin sensitivity in hypothalamic LEPRb-neurons. 2. Determine whether SH2-B regulates energy metabolism and body weight by directly modulating the activity of hypothalamic AgRP-neurons. 3. Determine whether SH2-B differentially regulates leptin sensitivity in the LEPRb-neurons governing energy intake versus energy expenditure.

描述（由申请人提供）：本研究项目的长期目标是阐明肥胖和肥胖相关代谢疾病的分子机制。肥胖是高血压、动脉粥样硬化、中风、心脏病发作、2型糖尿病和癌症的主要危险因素，这会降低寿命和生活质量。肥胖和肥胖相关疾病的医疗费用是巨大的，并继续迅速上升。最近发现的脂肪激素瘦素已经改变了我们对体重和能量平衡调节的理解。瘦素由脂肪组织产生，并按总脂肪量的比例分泌到血液中，结合并激活下丘脑中的瘦素受体，将外周营养信号传递给中枢神经系统。瘦素反应受损（瘦素抵抗）导致超重和肥胖。瘦素抵抗主要是由瘦素受体（LEPRb）下游的细胞信号传导抑制引起的。LEPRb结合并激活JAK 2，JAK 2是一种细胞质酪氨酸激酶，介导响应瘦素的关键信号传导途径。我们最近确定了SH 2-B，一个SH 2和PH结构域的衔接蛋白，作为JAK 2相互作用的蛋白在细胞中。我们推测SH 2-B是瘦素调节体重和能量平衡的关键增强子，并且SH 2-B表达和作用的缺陷可能是瘦素抵抗和肥胖的重要危险因素。为了验证这一假设，我们破坏了小鼠的SH 2-B基因。我们证明，SH 2-B基因敲除小鼠是严重的瘦素抵抗和肥胖。在这个建议中，我们将扩展我们的前期工作，并牢固地确立了SH 2-B在控制体重和能量稳态中的重要作用。我们将阐明SH 2-B作用的分子机制，采用生物化学，遗传学和生理学方法。本项目的研究结果将为通过靶向SH 2-B的表达和作用设计新的治疗肥胖和肥胖相关代谢疾病的治疗方法提供科学依据。具体目标是：1。确定SH 2-B是否通过直接增强下丘脑LEPRb神经元中的瘦素敏感性来调节能量代谢和体重。2.确定SH 2-B是否通过直接调节下丘脑AgRP神经元的活性来调节能量代谢和体重。3.确定SH 2-B是否在控制能量摄入与能量消耗的LEPRb神经元中差异调节瘦素敏感性。