SH2-B regulation of body weight and energy homostasis

描述（由申请人提供）：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，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，而且还在迅速上升。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，并按脂肪总量的比例分泌到血液中，它与下丘脑的受体结合并激活受体，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。瘦素抵抗主要是由于瘦素受体（LEPRb）下游细胞信号的抑制引起的。LEPRb结合并激活JAK2， JAK2是一种细胞质酪氨酸激酶，在瘦素反应中介导关键信号通路。我们最近发现SH2- b，一种含有SH2和PH结构域的衔接蛋白，是细胞中与jak2相互作用的蛋白。我们推测SH2-B是瘦素调节体重和能量稳态的关键增强因子，SH2-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SH2-B基因。我们证明SH2-B基因敲除小鼠有严重的瘦素抵抗和肥胖。在这一建议中，我们将扩展我们的前期工作，并牢固地确立SH2-B在控制体重和能量稳态中的重要作用。我们将从生物化学、遗传学和生理学的角度阐明SH2-B作用的分子机制。本项目研究结果将为设计针对SH2-B表达和作用治疗肥胖及肥胖相关代谢疾病的新疗法提供科学依据。具体目标是：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神经元的活性来调节能量代谢和体重。3. 确定SH2-B是否在控制能量摄入和能量消耗的leprb神经元中差异调节瘦素敏感性。

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.