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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）：