Role of mast cells in obesity

肥大细胞在肥胖中的作用

基本信息

批准号：
7583024
负责人：
GUO-PING SHI
金额：
$ 42.32万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583024
关键词：
Abdominal Aortic Aneurysm Adipocytes Adipose tissue Adult Affect Allergic Anti-Allergic Agents Aortic Aneurysm Atherosclerosis Biology Blood Vessels Body Weight Bone Marrow CCL2 gene Cathepsins Cell Adhesion Molecules Cells Chemotactic Factors Chymase Clinic Cromoglicic Acid Cysteine Protease Cytoplasmic Granules Development Diet Drug usage Effector Cell Exercise Extracellular Matrix Fatty acid glycerol esters Gelatinase B Genetic Growth Factor Homing Human Hypersensitivity In Vitro Incidence Individual Inflammation Inflammatory Intraperitoneal Injections Knockout Mice Knowledge LTB4R gene Leptin Leukotriene B4 Lymphocyte Maintenance Mast Cell Stabilizer Mediator of activation protein Metabolic Diseases Mus Names Obese Mice Obesity Operative Surgical Procedures Participant Patients Peptide Hydrolases Phenotype Production Public Health Reagent Role Serum Social Problems Testing Therapeutic Intervention Time Tryptase Vascular Diseases Visceral Weight Gain Wild Type Mouse adipocyte differentiation adipokines angiogenesis asthmatic patient base chemokine chemokine receptor cytokine glucose metabolism glucose tolerance improved insulin sensitivity lipid biosynthesis macrophage mast cell mouse model protein degradation public health relevance receptor reconstitution research study response

项目摘要

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.

描述（由申请人提供）：肥大细胞是通过释放细胞质颗粒引发过敏反应的重要效应细胞。我们最近的研究表明，肥大细胞参与过敏性炎症以外的人类病理学。肥大细胞缺乏或肥大细胞的药理稳定可显着降低小鼠实验性动脉粥样硬化和腹主动脉瘤的发生率。肥胖作为与动脉粥样硬化和主动脉瘤密切相关的代谢性疾病，不仅成为一个重要的科学课题，而且成为世界范围内严重的社会问题。我们首次揭示了肥胖人类和小鼠脂肪组织中肥大细胞的积累。使用肥大细胞缺陷小鼠模型或抗过敏肥大细胞稳定剂色甘酸，我们证明肥大细胞在肥胖中发挥着重要作用。肥大细胞缺陷型小鼠或用色甘酸处理的小鼠明显比对照小鼠更瘦，并且葡萄糖耐量显着增加。在肥大细胞缺陷小鼠或接受色甘酸治疗的小鼠中，除了体重增加减少和葡萄糖耐量增加之外，瘦素、趋化因子 MCP-1、细胞因子 TNF-a 和肥胖相关蛋白酶组织蛋白酶 S 的血清水平也降低。尽管肥大细胞导致肥胖的机制仍有待研究，但体外分化的肥大细胞可促进小鼠前脂肪细胞分化。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，从而导致肥胖、葡萄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葡萄糖代谢中的作用，并检查我们是否可以通过调节肥大细胞的激活来控制肥胖的进展和/或逆转小鼠预先形成的肥胖的表型。 2）。确定肥大细胞使用哪些趋化因子受体归巢至脂肪组织，并确定哪些常见的肥大细胞介质会导致肥胖。总之，这些实验应该提供强有力的证据，证明肥大细胞是否是肥胖所必需的，并从机制上解释肥大细胞如何影响这种常见的代谢紊乱。公共卫生相关性：肥胖是一个严重的公共卫生问题，影响着 30% 的美国成年人。尽管临床上通过体育锻炼和开放手术来减轻体重，但缺乏有效的肥胖非侵入性治疗方法。该提案检验了促炎性肥大细胞是肥胖的重要参与者这一假设，并彻底检验了我们是否可以通过调节肥大细胞活性来控制体重增加。