Metabolic effects of adipose lipogenesis

脂肪脂肪生成的代谢作用

基本信息

批准号：
8816092
负责人：
BARBARA B. KAHN
金额：
$ 61.73万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-25 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816092
关键词：
Address Adipocytes Adipose tissue Affect Age Animals Attention Binding Proteins Biochemical Biological Carbohydrates Cells Complement DNA Binding Data Diet Disease Down-Regulation Elements Enzymes Epidemic Event Fatty Acids Fatty acid glycerol esters Future Genomics Glucose Glucose Intolerance Glycolysis Goals Health Hepatocyte Human Insulin Insulin Resistance Knockout Mice Knowledge Lead Link Lipids Liver Metabolic Metabolic syndrome Metabolism Methods Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obese Mice Obesity Pancreas Paper Pathogenesis Pathway interactions Physiological Play Post-Translational Protein Processing Prevention strategy Protein Overexpression Proteins Publishing Quantitative Microscopy Regulation Relative (related person)Rodent Role Serum Therapeutic Tissues Work blood glucose regulation effective therapy glucose metabolism glucose transport glucose uptake human tissue improved insight insulin sensitivity insulin signaling knock-down lipid biosynthesis lipid metabolism novel novel therapeutic intervention overexpression prevent protein activation protein expression tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Major gaps exist in our knowledge of the molecular mechanisms underlying insulin resistance and type 2 diabetes. Dysregulation of both glucose and lipid metabolism play a role. This proposal investigates the mechanistic links between these pathways. Fatty acid synthesis (de novo lipogenesis, DNL) is elevated in liver in obesity and type 2 diabetes and is usually associated with insulin resistance. In contrast, our new data indicate DNL in adipose tissue is metabolically beneficial since it promotes insulin sensitivity an protects against high fat diet-induced insulin resistance. Furthermore, in humans, increased lipogenic enzyme expression in adipose tissue is associated with enhanced insulin sensitivity. One of the major transcriptional regulators of DNL is Carbohydrate responsive-element binding protein (ChREBP), a glucose-responsive transcription factor. ChREBP has been studied mainly in liver and pancreatic ¿ cells where it regulates fatty acid synthesis and glycolysis. ChREBP knockout mice have mild diet-related insulin resistance. However, knocking down the elevated ChREBP expression in liver of obese mice improves insulin sensitivity and metabolic syndrome. The effects of selective ChREBP knockdown in adipose tissue have not been studied. Our recent paper demonstrates that adipose tissue ChREBP is a key determinant of systemic insulin sensitivity and glucose homeostasis in humans and rodents. The goal of this application is to integrate whole animal and cellular studies to define the physiological, cellular and molecular mechanisms underlying the effects of ChREBP in adipose tissue to promote insulin sensitivity. We will create mice that overexpress or lack ChREBP selectively in adipocytes. Aim 1 is to determine whether increased expression of ChREBP selectively in adipocytes is sufficient to enhance systemic insulin sensitivity and improve glucose homeostasis. Aim 2 is to determine whether absence of ChREBP selectively in adipocytes causes systemic insulin resistance. In addition to physiological and metabolic characterization, in both aims we will perform genomic and lipidomic analyses of adipose tissue and serum to identify pathways associated with insulin sensitivity and insulin resistance. Aim 3 is to determine the cellular mechanisms by which ChREBP regulates de novo lipogenesis in adipocytes. Molecular, cell biological, biochemical and quantitative microscopy methods will be used to determine the mechanisms for regulation of ChREBP nuclear-cytoplasmic shuttling and activation in adipocytes, and the potential role of insulin signaling in regulation of adipose-ChREBP activity. Overall, this project will provide physiological, molecular, and cellular insights into ChREBP regulation. Because reduced ChREBP expression in adipose tissue of obese humans correlates highly with insulin resistance, understanding the mechanisms that regulate ChREBP in adipocytes could lead to novel therapeutic approaches to prevent and treat type 2 diabetes.

描述（由申请人提供）：我们对胰岛素抵抗和 2 型糖尿病的分子机制的了解存在重大差距，该提案研究了这些途径之间的机制联系。在肥胖和 2 型糖尿病中，肝脏中的从头脂肪生成 (DNL) 升高，通常与胰岛素抵抗相关。相反，我们在脂肪组织中的新数据表明，DNL 对代谢有益，因为它可以促进胰岛素敏感性并提供保护。此外，在人类中，脂肪组织中脂肪生成酶表达的增加与胰岛素敏感性的增强有关，碳水化合物反应元件结合蛋白（ChREBP）是一种葡萄糖反应元件。 ChREBP 主要在肝脏和胰腺中进行研究。 ChREBPout 敲除小鼠具有轻度的饮食相关胰岛素抵抗，然而，敲低肥胖小鼠肝脏中升高的 ChREBP 表达可改善脂肪组织中的胰岛素敏感性和代谢综合征。我们最近的论文表明，脂肪组织 ChREBP 是人类和啮齿动物全身胰岛素敏感性和葡萄糖稳态的关键决定因素。该应用的目标是整合整个动物和细胞研究。确定 ChREBP 在脂肪组织中促进胰岛素敏感性作用的生理、细胞和分子机制我们将创建在脂肪细胞中选择性过度表达或缺乏 ChREBP 的小鼠，目的 1 是确定脂肪细胞中选择性增加 ChREBP 的表达是否足够。目的 2 是确定脂肪细胞中选择性缺乏 ChREBP 是否会导致全身胰岛素抵抗。对脂肪组织和血清进行基因组和脂质组学分析，以确定与胰岛素敏感性和胰岛素抵抗相关的途径。目标 3 是确定 ChREBP 调节脂肪细胞从头脂肪生成的细胞机制。可用于确定脂肪细胞中 ChREBP 核质穿梭和激活的调节机制，以及胰岛素信号在脂肪-ChREBP 活性调节中的潜在作用。该项目将为 ChREBP 调节提供高度的生理学、分子和细胞见解，因为肥胖人群脂肪组织中 ChREBP 表达的减少与胰岛素抵抗相关，了解脂肪细胞中 ChREBP 的调节机制可能会带来预防和治疗 2 型的新治疗方法。糖尿病。