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.

摘要 腹部肥胖与一种易受胰岛素影响的慢性低度炎症密切相关 抵抗和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， 并与不同程度的代谢疾病有关。脂联素是一种脂肪因子，具有抗- 饮食诱导的炎症和胰岛素抵抗功能。虽然脂联素的有益作用主要是 在皮下脂肪组织中探讨脂联素对腹腔脏器的调控作用 炎症和肠系膜脂肪组织扩张仍然在很大程度上不清楚。拟议的研究旨在 阐明了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一个新靶点，含有17B的abhydrolase结构域， 脱棕榈酰酶（ABHD17 B）。目前研究的前提是基于我们在研究中的几个关键发现。 初步研究：1）Abhd17b基因在巨噬细胞中选择性表达，其表达量显著高于对照组， 在脂联素KO小鼠或高脂饮食喂养的小鼠中减少; 2）Abhd17 b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扩张; 3） Abhd17 b缺陷型巨噬细胞吞噬能力受损，炎症反应增强。这些数据 提示ABHD 17 B在介导脂联素在巨噬细胞中的抗炎作用中的作用。我们 总体假设是ABHD17 B下调诱导的巨噬细胞功能障碍可能是一个关键因素， 脂联素缺乏导致肥胖症代谢障碍的机制描述的研究 在这项提议中，将通过表征ABHD17 B在介导 脂联素的功能，并通过表征ABHD17 B介导的有益作用的机制， 脂联素的吞噬和抗炎作用。我们的多学科科学家团队将利用基因 小鼠模型和生物化学和基于细胞的测定来剖析ABHD 17 B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， 工作提供了一个独特的和创新的方法来询问功能的作用和监管的一个新的目标 脂联素ABHD17 B介导脂联素的抗炎和抗胰岛素抵抗作用。的 机制研究将有助于开发新的治疗腹部肥胖相关的代谢 包括2型糖尿病在内的疾病。