Adiponectin signaling and macrophage function

脂联素信号传导和巨噬细胞功能

基本信息

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
项目类别：
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

项目摘要

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密切相关，而慢性低度炎症容易产生胰岛素抵抗力和2型糖尿病的发展。内脏脂肪组织，特别是肠系膜脂肪组织，与皮下脂肪组织相比，表现出储库特异性免疫和代谢差异并与不同程度的代谢疾病有关。脂联素是一种脂肪因子，具有抗饮食引起的炎症和胰岛素抵抗功能。虽然脂联素的有益作用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扩张在很大程度上仍不清楚。拟议的研究旨在阐明脂联素信号在调节巨噬细胞功能和代谢稳态中的作用，专注于脂联素信号通路的新靶标，即含有 17B 的脱氢酶结构域去棕榈酰酶（ABHD17B）。当前研究的前提是基于我们的几项关键发现初步研究：1）Abhd17b基因在巨噬细胞中选择性表达；其表达量极大脂联素KO小鼠或高脂肪饮食喂养的小鼠中脂联素减少； 2) Abhd17b 缺乏会加剧饮食诱发的症状腹部肥胖、内脏器官炎症、胰岛素抵抗、肠系膜脂肪组织扩张； 3） Abhd17b 缺陷的巨噬细胞表现出吞噬能力受损和炎症加剧。这些数据提示 ABHD17B 在介导巨噬细胞中脂联素的抗炎功能中的作用。我们的总体假设是 ABHD17B 下调诱导的巨噬细胞功能障碍可能是关键脂联素缺乏引起的肥胖代谢障碍的机制。研究描述在本提案中，将通过表征 ABHD17B 在介导中的生理作用来检验这一假设脂联素功能以及 ABHD17B 介导有益作用的机制的表征脂联素的吞噬作用和抗炎作用。我们的多学科科学家团队将利用遗传小鼠模型以及生化和细胞分析，以剖析 ABHD17B 的功能和机制调节脂联素信号传导。鉴于腹部肥胖对人类健康的巨大影响，该建议工作提供了一种独特和创新的方法来质疑新目标的功能作用和监管脂联素 ABHD17B 介导脂联素的抗炎和抗胰岛素抵抗作用。这机制研究将有助于开发腹部肥胖相关代谢的新疗法疾病，包括 2 型糖尿病。