SH2-B regulation of body weight and energy homostasis

描述(申请人提供)：本研究计划的长期目标是阐明肥胖及肥胖相关代谢性疾病的分子机制。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风险因素，这些疾病会降低寿命和生活质量。肥胖和肥胖相关疾病的医疗成本是巨大的，而且还在继续快速上升。最近发现的脂肪激素瘦素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，与总脂肪质量成比例地分泌到血液中，与下丘脑中的受体结合并激活，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)会导致超重和肥胖。瘦素抵抗主要是由于瘦素受体(LEPRb)下游的细胞信号受抑制所致。LEPRb结合并激活JAK2，这是一种细胞质酪氨酸激酶，介导了响应瘦素的关键信号通路。我们最近发现SH2-B是一种含有SH2和PH结构域的接头蛋白，在细胞中是一种JAK2相互作用蛋白。我们推测SH2-B是瘦素调节体重和能量平衡的关键增强剂，SH2-B的表达和作用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，我们在小鼠身上破坏了SH2-B基因。我们证明SH2-B基因敲除小鼠是严重的瘦素抵抗和肥胖。在这项建议中，我们将延长我们的前期工作，并坚定地确立SH2-B在控制体重和能量平衡方面的重要作用。我们将用生化、遗传学和生理学的方法阐明SH2-B作用的分子机制。该项目的发现将为通过靶向SH2-B的表达和作用来设计肥胖和肥胖相关代谢性疾病的新治疗方法提供科学依据。具体目的：1.确定SH2-B是否通过直接增强下丘脑LEPRb神经元的瘦素敏感性来调节能量代谢和体重。2.确定SH2-B是否通过直接调节下丘脑AgRP神经元的活动来调节能量代谢和体重。3.确定SH2-B是否以不同方式调节LEPRb神经元中瘦素的敏感性，该神经元调节能量摄入与能量消耗。

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.