Leptin deficiency changes mast cell pro-inflammatory activity

瘦素缺乏会改变肥大细胞促炎活性

• 批准号: 9237291
• 负责人: GUO-PING SHI
• 金额: $ 40.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-10 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237291
• 关键词: Adipocytes; Adipose tissue; Adoptive Transfer; Adult; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Atherosclerosis; Basophils; Body Weight; Bone Marrow; Cells; Chronic; Dendritic Cells; Development; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Energy Metabolism; Genetic; Homeostasis; Hormones; Human; Inflammation; Inflammation Mediators; Inflammatory; Interruption; Knockout Mice; Leptin; Leptin deficiency; Leukocytes; Low Density Lipoprotein Receptor; Maintenance; Metabolic; Metabolic Diseases; Molecular; Mus; Obese Mice; Obesity; Pathogenesis; Phenotype; Plasma; Population; Regulatory T-Lymphocyte; Reverse Transcriptase Polymerase Chain Reaction; Role; Satiation; Signal Transduction; Smooth Muscle Myocytes; T cell differentiation; T-Lymphocyte; Testing; Thinness; Weight Gain; Wild Type Mouse; base; cytokine; experimental study; improved; increased appetite; insulin sensitivity; lean body mass; macrophage; mast cell; monocyte; neutrophil; novel; polarized cell; public health relevance; receptor; response; small hairpin RNA

 DESCRIPTION (provided by applicant): Mast cells (MCs) participate in cardiometabolic diseases, including obesity, diabetes, and atherosclerosis, that affect more than one-third of the American adult population. MC deficiency or inactivation protects mice from these cardiometabolic diseases. The pro-inflammatory hormone leptin, acts as a satiety factor that regulates body weight gain by suppressing appetite and stimulating energy expenditure. While inflammatory cytokines induce adipocyte leptin expression, this hormone also activates most other tested cells, including those closely related to cardiometabolic diseases, such as dendritic cells, basophils, monocytes/macrophages, smooth muscle cells (SMCs), endothelial cells (ECs), neutrophils, and effector and regulatory T cells. MCs also express leptin and its receptor. Obese humans have elevated plasma leptin levels that associate with white adipose tissue (WAT) inflammation and MC accumulation. Our preliminary studies revealed unexpected observations: WAT from lean humans and mice contained much more leptin than WAT from obese humans and diet-induced obese (DIO) mice, but MCs in WAT from lean humans and mice expressed negligible leptin, significantly less than MCs from obese humans and mice. In the absence of MCs, leptin-deficient ob/ob mice gained significantly more body weight and developed worse diabetes than MC-sufficient ob/ob mice. In MC-deficient KitW-sh/W-sh mice, reduced body weight and improved diabetes can all be reversed by the adoptive transfer of bone marrow-derived MCs (BMMCs) from wild-type (WT) mice, but not those from ob/ob mice. FACS analysis and RT-PCR of WAT from KitW-sh/W-sh mice revealed reduced classically activated M1 macrophages and increased alternatively activated M2 macrophages, a profile fully reversible by WT BMMCs but not ob/ob BMMCs. These preliminary results suggest that leptin-deficient MCs polarize M2 macrophages, which produce anti-inflammatory cytokines, associate with lean body mass and metabolic homeostasis, and contribute to insulin sensitivity maintenance. The study of cultured bone marrow-derived macrophages indicated that leptin-deficient BMMCs but not WT BMMCs tipped macrophage towards M2 polarization. Based on our preliminary studies, we hypothesize that deficient leptin expression in MCs may shift cell profiles from pro-inflammatory to anti-inflammatory functions; and that such cells may ameliorate cardiometabolic diseases (e.g. obesity, diabetes, and atherosclerosis) by promoting M2 polarization and probably anti-inflammatory T- cell differentiation in WAT, arteries, or other inflammatory states that involve MCs. We propose three aims to test this hypothesis: to examine whether leptin-deficient mast cells protect mice from obesity and diabetes; to investigate the cellular and molecular mechanisms by which leptin-deficient MCs protect mice from obesity and diabetes and; to examine whether leptin-deficient MCs also exert anti-inflammatory activities in other inflammatory diseases, such as atherosclerosis.

 描述（由申请人提供）：肥大细胞 (MC) 参与心脏代谢疾病，包括肥胖、糖尿病和动脉粥样硬化，这些疾病影响超过三分之一的美国成年人，MC 缺乏或失活可以保护小鼠免受这些心脏代谢疾病的影响。促炎激素瘦素，作为一种饱腹感因子，通过抑制食欲和刺激能量消耗来调节体重增加，而炎症细胞因子会诱导脂肪细胞瘦素表达，这种激素也会影响体重。激活大多数其他测试细胞，包括那些与心脏代谢疾病密切相关的细胞，如树突状细胞、嗜碱性粒细胞、单核细胞/巨噬细胞、平滑肌细胞 (SMC)、内皮细胞 (EC)、中性粒细胞以及效应 T 细胞和调节性 T 细胞。瘦素及其受体。肥胖人群的血浆瘦素水平升高，这与白色脂肪组织 (WAT) 炎症和 MC 积聚有关。观察结果：瘦人和小鼠的 WAT 比肥胖和饮食诱导肥胖 (DIO) 小鼠的 WAT 含有更多的瘦素，但瘦人和小鼠的 WAT 中的 MC 表达的瘦素可以忽略不计，显着低于肥胖人和小鼠的 MC。在缺乏 MC 的情况下，缺乏瘦素的 ob/ob 小鼠比 MC 充足的 ob/ob 小鼠体重明显增加，并且患上更严重的糖尿病。 KitW-sh/W-sh 小鼠的体重减轻和糖尿病改善都可以通过过继转移来自野生型 (WT) 小鼠的骨髓来源的 MC (BMMC) 来逆转，但来自 ob/ob 小鼠的骨髓来源的 MC 则不能逆转。对 KitW-sh/W-sh 小鼠 WAT 进行 FACS 分析和 RT-PCR，结果显示经典激活的 M1 巨噬细胞减少，替代激活的 M2 巨噬细胞增加，这一特征可被 WT BMMC 完全逆转，但不可逆 ob/ob这些初步结果表明，缺乏瘦素的 MC 会极化 M2 巨噬细胞，从而产生抗炎细胞因子，与瘦体重和代谢稳态相关，并有助于维持胰岛素敏感性。对培养的骨髓源性巨噬细胞的研究表明，瘦素缺乏。 -缺陷的 BMMC 而不是 WT BMMC 使巨噬细胞倾向于 M2 极化。根据我们的初步研究，我们发现 MC 中瘦素表达缺陷可能会导致巨噬细胞极化。将细胞功能从促炎功能转变为抗炎功能；并且这些细胞可以通过促进 WAT、动脉、我们提出了三个目标来检验这一假设：检查瘦素缺乏的肥大细胞是否可以保护小鼠免受肥胖和糖尿病的影响；研究瘦素缺乏的细胞和分子机制。 MC 可以保护小鼠免受肥胖和糖尿病的影响，并检查缺乏瘦素的 MC 是否也在其他炎症性疾病（例如动脉粥样硬化）中发挥抗炎活性。