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

• 批准号: 7660570
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660570
• 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

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）： 虽然我之前的K 08申请得到了好评，但有一些关键问题。为了解决这些问题，我提出了一个明显改进的建议。我的目的是探索DGAT 1如何调节白色脂肪组织（WAT）的代谢，以及巨噬细胞或脂肪细胞是否在这种调节中占主导地位。这些目的部分基于观察到脂肪细胞/巨噬细胞区室中DGAT 1基因（Dgat 1）的表达增加可增强高脂饮食转基因小鼠（aP 2-Dgat 1）的葡萄糖耐量。此后，我扩大了这些发现，表明这些小鼠受到保护，免受经典（M1）炎症激活和巨噬细胞在WAT中的积累。此外，Dgat 1在巨噬细胞中的表达与TG储存直接相关，与饱和棕榈酸激活的M1相反。因此，我完成了Subaims 2.1，2.3和2.2的部分，这些数据被提交出版。这项工作还提出了一种假设，即巨噬细胞、脂肪细胞或这两种细胞类型中的细胞内FA以DGAT 1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，它比以前的目标具有明显的优势。发现DGAT 1缺陷型（Dgat 1-/-）巨噬细胞易受棕榈酸盐激活M1的影响，表明巨噬细胞中DGAT 1缺陷可能在体内有害。另一方面，aP 2-Dgat 1转基因小鼠受到保护，免受DIO的炎症和代谢后果，尽管尚不清楚脂肪细胞和巨噬细胞如何对此做出贡献。我已经获得了增加或减少Dgat 1表达的小鼠模型，特别是在巨噬细胞或脂肪细胞中，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探讨了细胞内脂肪酸和DGAT 1相互作用调节巨噬细胞活化的机制，新的目标3侧重于脂肪细胞和巨噬细胞之间的相互作用。我的策略使用Dgat 1 mRNA水平的操纵作为一种工具，以确定脂肪酸如何调节脂肪细胞和巨噬细胞的功能。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：确定细胞内脂肪酸如何调节巨噬细胞活化可能会产生新的临床目标，直接适用于肥胖和糖尿病。鉴于高脂饮食的流行，确定哪些细胞内脂肪酸刺激巨噬细胞活化是重要的。确定DGAT 1如何调节巨噬细胞和脂肪细胞对FA的反应将有助于评估DGAT 1抑制剂在试验中的临床潜力。