Role of mast cells in obesity

描述(申请人提供)：肥大细胞是通过释放细胞质颗粒来激发过敏反应的基本效应细胞。我们最近的研究表明，肥大细胞参与了人类的病理生物学，而不仅仅是过敏性炎症。肥大细胞缺乏或肥大细胞的药理稳定可显著降低小鼠实验性动脉粥样硬化和腹主动脉瘤的发生率。肥胖作为一种与动脉粥样硬化和主动脉瘤密切相关的代谢紊乱，不仅是一个重要的科学问题，而且是一个严重的世界性社会问题。我们第一次发现肥大细胞在肥胖的人类和小鼠的脂肪组织中积累。利用肥大细胞缺陷小鼠模型或抗过敏肥大细胞稳定剂Cromolyn，我们证明了肥大细胞在肥胖中起重要作用。肥大细胞缺陷小鼠或使用色甘露治疗的小鼠明显比对照组小鼠瘦，并表现出显著的葡萄糖耐量增加。在体重增加和糖耐量增加的同时，肥大细胞缺陷小鼠或接受色甘宁治疗的小鼠血清瘦素、趋化因子单核细胞趋化蛋白-1、细胞因子肿瘤坏死因子-α和肥胖相关组织蛋白酶S的水平也降低。尽管肥大细胞促进肥胖的机制仍有待研究，但在体外分化的肥大细胞促进小鼠前脂肪细胞的分化。因此，我们的中心假设是肥大细胞产生促炎细胞因子和蛋白酶来调节脂肪组织和细胞外基质的生物学，从而促进肥胖、糖耐量和胰岛素敏感性。提出了两个具体目标：1)。研究肥大细胞在体重增加和糖代谢中的作用，并探讨能否通过调节肥大细胞的激活来控制肥胖的进展和/或逆转小鼠先天肥胖的表型。2)。确定肥大细胞使用哪些趋化因子受体来归巢到脂肪组织，并确定哪些常见的肥大细胞介质与肥胖有关。总之，这些实验应该会提供肥大细胞是否是肥胖所必需的强有力的证据，并为肥大细胞如何影响这种常见的代谢紊乱提供机械性的解释。 与公共健康相关：肥胖是一个严重的公共健康问题，影响着美国30%的成年人。虽然临床上使用体育锻炼和开放手术来减轻体重，但缺乏有效的非侵入性肥胖治疗方法。这项建议检验了促炎肥大细胞是肥胖的重要参与者的假设，并彻底检查了我们是否可以通过调节肥大细胞的活动来管理体重增加。

DESCRIPTION (provided by applicant): Mast cells are essential effector cells in the elicitation of the allergic responses by releasing cytoplasmic granules. Our recent studies suggest that mast cells participate in human pathobiology beyond allergic inflammation. Mast cell deficiency or pharmacological stabilization of mast cells reduces significantly the incidences of experimental atherosclerosis and abdominal aortic aneurysms in mice. As a close associated metabolic disorder of atherosclerosis and aortic aneurysms, obesity becomes not just an important scientific topic, but also a serious social problem worldwide. For the first time, we revealed accumulation of mast cells in adipose tissues from obese humans and mice. Using mast cell-deficient mouse model or anti-allergy mast cell stabilizer cromolyn, we demonstrated that mast cells are important player in obesity. Mast cell-deficient mice or those treated with cromolyn are significantly leaner than the control mice and show significant increase of glucose tolerance. Along with reduced body weight gain and increased glucose tolerance, serum levels of leptin, chemokine MCP-1, cytokine TNF-a, and obesity pertinent protease cathepsin S are also reduced in mast cell-deficient mice or those received cromolyn treatment. Although a mechanism by which mast cells contribute to obesity remains to be investigated, in vitro differentiated mast cells promote mouse pre-adipocyte differentiation. Thus, our central hypothesis is that mast cells produce pro-inflammatory cytokines and proteases to modulate the biology of adipose tissue and the extracellular matrix, thereby contributing to obesity, glucose tolerance and insulin sensitivity. Two specific aims are proposed: 1). To study the role of mast cells in body weight gain and glucose metabolism and to examine whether we can control the progression of obesity and/or reverse the phenotypes of pre-formed obesity in mice by regulating mast cell activations. 2). To identify which chemokine receptors that mast cells use for homing to the adipose tissues and to identify which of those common mast cell mediators contributes to obesity. Together, these lines of experiments should provide strong evidence of whether mast cells are required for obesity and mechanistic explanations of how mast cells might influence this common metabolic disorder. PUBLIC HEALTH RELEVANCE: Obesity is a serious public health problem that affects 30% of adults in the US. Although physical exercise and open surgery are used in the clinic to reduce the body weight, effective non-invasive therapy of obesity lacks. This proposal tests the hypothesis that pro-inflammatory mast cells are important participants of obesity, and examines thoroughly whether we can manage body weight gain by regulating mast cell activity.