DGAT1: Linking Fatty Acids to Inflammation and Metabolism in White Adipose Tissue

DGAT1：脂肪酸与白色脂肪组织炎症和代谢的联系

基本信息

批准号：
7794843
负责人：
SUNEIL Krishna KOLIWAD
金额：
$ 15.46万
依托单位：
J. DAVID GLADSTONE INSTITUTES
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：
2009-04-01 至 2011-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7794843
关键词：
Acyl Coenzyme A Address Adipocytes Adipose tissue Affect Apoptosis Apoptotic Attention Bone Marrow Transplantation Cell Death Cell surface Cells Cessation of life Chemotaxis Chronic Clinical Coculture Techniques Data Dental crowns Development Diabetes Mellitus Diet Dietary Fatty Acid Enzymes Fatty Acids Fatty acid glycerol esters Genes Hand High Prevalence Inflammation Inflammatory Insulin Resistance Link Lipolysis Macrophage Activation Mediating Mentors Messenger RNA Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mus Nutritional Obesity Palmitates Palmitic Acids Phagocytosis Phenotype Principal Investigator Process Publications Research Role Saturated Fatty Acids Structure TLR10 gene Testing Tissues Toll-like receptors Transgenic Mice Triglycerides Work base cell type diacylglycerol O-acyltransferase endoplasmic reticulum stress extracellular feeding field study fluorescence imaging glucose tolerance improved in vivo inhibitor/antagonist mRNA Expression macrophage mouse model paracrine public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): Though my prior K08 application was scored favorably, there were some key concerns. In addressing these, I developed a markedly improved proposal. I had aimed to explore how DGAT1 modulates metabolism in the white adipose tissue (WAT), and whether macrophages or adipocytes are dominant in this modulation. These Aims were based in part on observing that increased expression of the DGAT1 gene (Dgat1) in the adipocyte/macrophage compartment enhanced glucose tolerance in transgenic mice (aP2-Dgat1) on a high-fat diet. I have since expanded these findings, showing that these mice are protected against classical (M1) inflammatory activation and accumulation of macrophages in WAT. Further, Dgat1 expression in macrophages correlated directly with TG storage and inversely with M1 activation by saturated palmitic acid. I thus completed Subaims 2.1, 2.3, and part of 2.2 from the initial proposal, and these data were submitted for publication. This work also prompted the hypothesis that intracellular FAs, in macrophages, adipocytes, or both cell types, regulate inflammatory and metabolic pathways in a DGAT1-sensitive manner. I propose to test this hypothesis in revised Aims with distinct advantages over the prior ones. Finding that DGAT1-deficient (Dgat1-/-) macrophages are vulnerable to M1 activation by palmitate suggests that DGAT1 deficiency in macrophages could be deleterious in vivo. On the other hand, aP2-Dgat1 transgenic mice were protected against the inflammatory and metabolic consequences of DIO, though it is unknown how adipocytes and macrophages contribute to this. I have obtained mouse models to increase or decrease Dgat1 expression specifically in macrophages or adipocytes and will test how each manipulation affects inflammation and metabolism in the revised Aim 1. The revised Aim 2 explores the mechanisms by which intracellular FAs and DGAT1 interact to modulate macrophage activation, and a new Aim 3 focuses on the cross-talk between adipocytes and macrophages. My strategy uses manipulation of Dgat1 mRNA level as a tool to determine how FAs regulate adipocyte and macrophage function. This approach will allow me to enter a new field of study that is entirely distinct from that of my mentor's lab. PUBLIC HEALTH RELEVANCE: Determining how intracellular FAs regulate macrophage activation may yield new clinical targets directly applicable to obesity and diabetes. Identifying which intracellular FAs stimulate macrophage activation is important given the prevalence of high-fat diets. Determining how DGAT1 modulates the response of macrophages and adipocytes to FAs will aid in evaluating the clinical potential of DGAT1 inhibitors in trials.

描述（由申请人提供）：尽管我之前的 K08 申请获得了不错的分数，但还是存在一些关键问题。为了解决这些问题，我提出了一个显着改进的提案。我的目的是探索 DGAT1 如何调节白色脂肪组织 (WAT) 的新陈代谢，以及巨噬细胞还是脂肪细胞在这种调节中占主导地位。这些目标部分基于观察到脂肪细胞/巨噬细胞区室中 DGAT1 基因 (Dgat1) 表达的增加增强了高脂肪饮食转基因小鼠 (aP2-Dgat1) 的葡萄糖耐量。此后我扩展了这些发现，表明这些小鼠可以免受经典 (M1) 炎症激活和 WAT 中巨噬细胞积聚的影响。此外，巨噬细胞中的 Dgat1 表达与 TG 储存直接相关，与饱和棕榈酸的 M1 激活成反比。因此，我完成了最初提案中的 Subaims 2.1、2.3 和 2.2 的一部分，并将这些数据提交出版。这项工作还提出了这样的假设：巨噬细胞、脂肪细胞或这两种细胞类型中的细胞内 FA 以 DGAT1 敏感的方式调节炎症和代谢途径。我建议在修订后的目标中检验这一假设，该目标比之前的目标具有明显的优势。发现 DGAT1 缺陷 (Dgat1-/-) 巨噬细胞容易受到棕榈酸酯激活 M1 的影响，这表明巨噬细胞中 DGAT1 缺陷可能在体内有害。另一方面，aP2-Dgat1 转基因小鼠受到保护，免受 DIO 的炎症和代谢后果的影响，尽管目前尚不清楚脂肪细胞和巨噬细胞如何促成这一结果。我已经获得了专门增加或减少巨噬细胞或脂肪细胞中 Dgat1 表达的小鼠模型，并将在修订后的目标 1 中测试每种操作如何影响炎症和代谢。修订后的目标 2 探索细胞内 FA 和 DGAT1 相互作用调节巨噬细胞活化的机制，新的 Aim 3 重点关注脂肪细胞和巨噬细胞之间的串扰。我的策略使用操纵 Dgat1 mRNA 水平作为确定 FA 如何调节脂肪细胞和巨噬细胞功能的工具。这种方法将使我进入一个与我导师实验室完全不同的新研究领域。公共卫生相关性：确定细胞内 FA 如何调节巨噬细胞活化可能会产生直接适用于肥胖和糖尿病的新临床目标。鉴于高脂肪饮食的盛行，识别哪些细胞内 FA 刺激巨噬细胞活化非常重要。确定 DGAT1 如何调节巨噬细胞和脂肪细胞对 FA 的反应将有助于评估 DGAT1 抑制剂在试验中的临床潜力。