Insulin Signaling and Metabolic Regulation in Adipocytes

脂肪细胞中的胰岛素信号传导和代谢调节

基本信息

批准号：
9104142
负责人：
MICHAEL P CZECH
金额：
$ 51.93万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104142
关键词：
Address Adhesions Adipocytes Adipose tissue Animal Model Beta Cell Blood Vessels Cardiovascular system Cell Adhesion Molecules Cell model Cell surface Cells Comorbidity Complex Data Defect Deposition Diabetes Mellitus Disease E-Selectin Endothelial Cells Esterification Evaluation Exhibits Extravasation FRAP1 gene Fatty Acids Fatty Liver Fatty acid glycerol esters Figs - dietary Functional disorder Funding Glucose Glucose Intolerance Health Homeostasis Human Immune system In Vitro Individual Infiltration Insulin Insulin Resistance Knock-out Knockout Mice Laboratories Lead Leukocyte Adhesion Molecules Leukocyte-Adhesion Receptors Leukocytes Lipid Synthesis Pathway Lipids Lipolysis Liver LoxP-flanked allele Maps Mediating Metabolic Metabolic Pathway Metabolism Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Orthologous Gene Pathway interactions Peripheral Permeability Phenocopy Phosphotransferases Physiological Process Protein Kinase Proteins Reagent Regulation Risk Role Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA T-Lymphocyte Testing Tissues Triglycerides Up-Regulation Vascular Cell Adhesion Molecule-1 adiponectin base cell type cytokine glucose tolerance glucose transport human subject in vivo insight insulin signaling intercellular cell adhesion molecule knock-down lipid biosynthesis macrophage mouse model promoter research study response small hairpin RNA transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): This project, which has been continuously funded for 30 years, addresses adipose metabolism that controls whole body glucose and lipid homeostasis in health and disease. Co-morbidities associated with obesity, including insulin resistance and type 2 diabetes, can result from insufficient deposition and storage of triglyceride (TG) within adipose tissue, leading to deleterious effects on liver, skeletal muscle, cardiovascular organs and insulin secreting beta cells. Thus a high capacity of adipose tissue for fatty acid esterification and sequestration of TG is vital during caloric surplus. However, thi function of adipocytes involves complex and incompletely understood interactions with macrophages and other cells of the immune system that infiltrate adipose tissue in obesity. Three key mechanistic questions are: What are the major signaling pathways that regulate fatty acid esterification and TG sequestration in adipocytes? How do macrophages modulate these pathways of adipocyte lipid storage? What controls macrophage infiltration into adipose tissue? This project previously employed siRNA screens to discover the Ste20 ortholog Map4k4, a protein kinase we discovered is integral to all three questions. Based on our recent exciting data, we now hypothesize that 1. Map4k4 in adipocytes, activated by macrophage cytokines, markedly suppresses adipocyte fatty acid esterification and TG sequestration, 2. Knockout of Map4k4 in adipocytes in mice will enhance TG storage in adipose tissue and increase glucose tolerance and decrease fatty liver, and 3. Map4k4 in adipose endothelial cells mediates upregulation of adhesion molecules that promote macrophage extravasation. We propose to identify and define the Map4k4 signaling pathways for lipogenic suppression in adipocytes in vitro (Aim 1) and in vivo (Aim 2) and for activation of endothelial cell permeability (Aim 3). We will define the specific roles of PPARg, SREBP1c and ChREBP as targets of Map4k4 regulation in adipocytes, and utilize two floxed mouse models we already generated wherein Map4k4 is selectively silenced (shRNA) or ablated in adipocytes or endothelial cells, respectively. We will test whether increased lipogenesis in adipose specific Map4k4 KO mice results in increased glucose tolerance, and whether adhesion molecule expression and macrophage extravasation is inhibited in endothelial specific KO mice. These experiments will provide important insights into adipose lipid handling in metabolic regulation and Map4k4 signaling in cross talk among cell types within adipose tissue.

描述（由申请人提供）：该项目已连续资助了30年，它涉及控制全身葡萄糖和脂质稳态中健康和疾病中的脂肪代谢。与肥胖相关的合并症，包括胰岛素抵抗和2型糖尿病，可能是由于甘油三酸酯的沉积和储存不足而导致的（TG）在脂肪组织中，导致对肝脏，骨骼肌，心血管器官和胰岛素分泌β细胞的有害作用。因此，在热量盈余期间，高脂肪组织用于脂肪酸酯化和TG隔离至关重要。然而，脂肪细胞的功能涉及复杂且不完全理解与肥胖症中浸润脂肪组织的巨噬细胞和其他细胞的相互作用。三个关键的机械问题是：调节脂肪酸酯化和TG固相的主要信号通路是什么？巨噬细胞如何调节这些脂肪细胞脂质储存的途径？是什么控制巨噬细胞浸润到脂肪组织中？该项目以前使用siRNA屏幕来发现Ste20 Ortholog Map4K4，我们发现的蛋白激酶是所有三个问题不可或缺的一部分。基于我们最近的令人兴奋的数据，我们现在假设脂肪细胞激活的1。map4k4在巨噬细胞因子激活中，显着抑制了脂肪细胞脂肪酸酯酯和TG隔离，2。敲除MAP4K4的MAP4K4在小鼠中的脂肪细胞中的MAP4K4在小鼠中的脂肪细胞中会增强TG的储存量，并在脂肪中增强脂肪的脂肪量，并降低脂肪的脂肪量和降低glke 4 and glke and live 4脂肪内皮细胞介导促进巨噬细胞渗出的粘附分子的上调。我们建议识别并定义MAP4K4信号传导途径，用于体外脂肪细胞（AIM 1）和体内（AIM 2）以及激活内皮细胞通透性（AIM 3）的MAP4K4信号传导途径。我们将将PPARG，SREBP1C和CHREBP的特定作用定义为脂肪细胞中MAP4K4调节的靶标，并利用我们已经生成的两个Floxed小鼠模型，其中MAP4K4分别在脂肪细胞或内皮细胞中分别在脂肪细胞或内皮细胞中被消化。我们将测试是否会增加脂肪特异性MAP4K4 KO小鼠的脂肪生成会导致葡萄糖耐量增加，以及在内皮特异性KO小鼠中是否抑制了粘附分子表达和巨噬细胞的渗出。这些实验将提供对代谢调节中脂肪脂质处理的重要见解，而MAP4K4信号在脂肪组织中的细胞类型之间进行了交谈。