Adiponectin signaling and macrophage function

脂联素信号传导和巨噬细胞功能

• 批准号: 10735952
• 负责人: Lily Q Dong
• 金额: $ 52.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735952
• 关键词: Acyltransferase; Adipose tissue; Affect; Agonist; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptotic; Biochemical; Biological Assay; Cells; Central obesity; Chronic; Data; Development; Diet; Down-Regulation; Enzymes; Exhibits; Fatty Liver; Functional disorder; Genes; Genetic; Grant; Greater sac of peritoneum; Health; High Fat Diet; Homeostasis; Human; Immune; Immunology; Impairment; Individual; Inflammation; Inflammatory; Injections; Insulin; Insulin Resistance; Knockout Mice; Lecithin; Link; Lysophosphatidylcholines; Macrophage; Mammals; Mediating; Mesentery; Metabolic; Metabolic Diseases; Metabolism; Mission; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Obesity associated disease; Organ; Organism; Pathway interactions; Phagocytes; Phagocytosis; Phenotype; Physiological; Positioning Attribute; Proteins; Public Health; Regulation; Role; Scientist; Signal Pathway; Signal Transduction; Testing; Tissue Expansion; United States National Institutes of Health; Visceral; Work; adipokines; adiponectin; in vivo; innovation; insight; membrane biogenesis; mouse model; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; palmitoylation; prevent; proteostasis; rapid growth; receptor; selective expression; subcutaneous; systemic inflammatory response; therapy development; tool

Abstract Abdominal obesity is tightly associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. Visceral adipose tissues, especially mesenteric adipose tissue, exhibit depot-specific immune and metabolic differences compared with subcutaneous adipose tissue and has been linked to varying degrees of metabolic diseases. Adiponectin is an adipokine that possesses anti- diet-induced inflammation and insulin resistance functions. While the beneficial role of adiponectin is largely explored in subcutaneous adipose tissue, the role of adiponectin in controlling peritoneal cavity organ inflammation and mesenteric adipose tissue expansion remains largely unclear. The proposed study aims at elucidating the role of adiponectin signaling in regulating macrophage function and metabolic homeostasis, focusing on a new target of the adiponectin signaling pathway, the abhydrolase domain containing 17B depalmitoylase (ABHD17B). The premise of the current study is based on several key findings made in our preliminary studies: 1) the Abhd17b gene is selectively expressed in macrophage; its expression is greatly reduced in adiponectinKO mice or high fat diet-fed mice; 2) Abhd17b deficiency exacerbates diet-induced abdominal obesity, visceral organ inflammation, insulin resistance, and mesenteric adipose tissue expansion; 3) Abhd17b deficient macrophage displayed impaired phagocytic ability and augmented inflammation. These data suggest the role of ABHD17B in mediating the anti-inflammatory function of adiponectin in macrophage. Our overarching hypothesis is that ABHD17B downregulation-induced macrophage dysfunction may be a key mechanism underlying adiponectin deficiency-induced metabolic impairment in obesity. The studies described in this proposal will test this hypothesis by characterizing the physiological roles of ABHD17B in mediating adiponectin function and by characterizing the mechanism by which ABHD17B mediates the beneficial effects of adiponectin on phagocytosis and anti-inflammation. Our multidisciplinary team of scientists will use genetic mouse models and biochemical and cell-based assays to dissect the function and mechanism of ABHD17B in regulating adiponectin signaling. Given the vast impact of abdominal obesity on human health, this proposed work offers a unique and innovative approach to interrogate the functional roles and regulation of a new target of adiponectin, ABHD17B, in mediating the anti-inflammation and anti-insulin resistant roles of adiponectin. The mechanistical studies will help to develop new therapeutic treatment of abdominal obesity related metabolic diseases including type 2 diabetes.

抽象的 腹部肥胖与慢性低度炎症紧密相关，这种炎症易于胰岛素 抗药性和2型糖尿病的发展。内脏脂肪组织，尤其是肠系膜脂肪 与皮下脂肪组织相比，组织表现出仓库特异性的免疫和代谢差异 并与不同程度的代谢疾病有关。脂联素是一种脂蛋白，具有抗 饮食引起的炎症和胰岛素抵抗功能。脂联素的有益作用在很大程度上是 在皮下脂肪组织中探索，脂联素在控制腹膜腔器官中的作用 炎症和肠系膜脂肪组织的扩张在很大程度上不清楚。拟议的研究旨在 阐明脂联素信号传导在调节巨噬细胞功能和代谢稳态中的作用， 关注脂联素信号通路的新靶标，含有17B 去氨木叶霉菌酶（ABHD17B）。当前研究的前提是基于我们的几个关键发现 初步研究：1）ABHD17B基因在巨噬细胞中有选择地表达；它的表达极为 在脂肪卷科小鼠或高脂肪饮食喂养小鼠中减少； 2）ABHD17B缺乏加剧饮食诱导的 腹部肥胖，内脏器官炎症，胰岛素抵抗和肠系膜脂肪组织膨胀； 3） ABHD17B缺乏巨噬细胞表现出受损的吞噬能力和增强的炎症。这些数据 建议ABHD17B在介导脂联素在巨噬细胞中的抗炎功能中的作用。我们的 总体假设是ABHD17B下调引起的巨噬细胞功能障碍可能是关键 脂肪蛋白缺乏诱导的肥胖症的代谢障碍的机制。描述的研究 在此提案中，将通过表征ABHD17B的生理作用来检验这一假设 脂联素功能并表征ABHD17B介导有益作用的机制 脂联素对吞噬作用和抗炎。我们的多学科科学家团队将使用遗传 小鼠模型以及生化和基于细胞的测定法，以剖析ABHD17B在 调节脂联素信号传导。考虑到腹部肥胖对人类健康的巨大影响，这提出了 工作提供了一种独特而创新的方法来审问新目标的功能角色和调节 脂联素，ABHD17B的介导脂联素的抗炎和抗胰岛素耐药作用。这 机械研究将有助于开发与腹部肥胖相关代谢的新治疗治疗 包括2型糖尿病的疾病。