Metabolic effects of adipose lipogenesis

脂肪脂肪生成的代谢作用

• 批准号: 8626395
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-25 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626395
• 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; 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; public health relevance; tool; transcription factor

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（由适用提供）：我们对胰岛素抵抗和2型糖尿病的分子机制的了解中存在主要差距。葡萄糖和脂质代谢的失调起着作用。该提案研究了这些途径之间的机械联系。肥胖症和2型糖尿病的肝脏脂肪酸合成（从头脂肪生成，DNL）升高，通常与胰岛素抵抗有关。对比，我们的新数据表明脂肪组织中的DNL在代谢上是有益的，因为它促进了胰岛素敏感性，可以预防高脂饮食诱导的胰岛素耐药性。此外，在人类中，脂肪组织中脂肪生成酶的表达增加与胰岛素敏感性增强有关。 DNL的主要转录调节剂之一是碳水化合物响应元素结合蛋白（CHREBP），一种葡萄糖反应转录因子。 CHREBP主要研究在肝脏和胰腺细胞中调节脂肪酸合成和糖酵解。 Chrebp敲除小鼠具有与饮食相关的轻度胰岛素抵抗。然而，击倒肥胖小鼠肝脏中Chrebp升高的表达提高了胰岛素敏感性和代谢综合征。选择性Chrebp敲低在脂肪组织中的影响尚未研究。我们最近的论文表明，脂肪组织Chrebp是人类和啮齿动物中全身性胰岛素敏感性和葡萄糖稳态的关键。该应用的目的是整合整个动物和细胞研究，以定义Chrebp在脂肪组织中影响的物理，细胞和分子机制，以促进胰岛素敏感性。我们将在脂肪细胞中选择性地产生过表达或缺乏Chrebp的小鼠。目的1是确定在脂肪细胞中选择性增加Chrebp是否足以提高全身性胰岛素敏感性并改善葡萄糖稳态。目的2是确定在脂肪细胞中有选择性地缺乏Chrebp会引起全身性胰岛素抵抗。除了物理和代谢表征外，在这两个目的中，我们都将对脂肪组织和血清进行基因组和脂质组分析，以鉴定与胰岛素敏感性和胰岛素抵抗相关的途径。目的3是确定Chrebp调节脂肪细胞中从头脂肪形成的细胞机制。分子，细胞生物学，生化和定量显微镜方法将用于确定脂肪细胞中CHREBP核胞质穿梭和激活的调节机制，以及胰岛素信号在调节脂肪糖 - chrebp活性调节中的潜在作用。总体而言，该项目将为Chrebp调节提供生理，分子和细胞的见解。由于肥胖人类脂肪组织中的Chrebp表达降低与胰岛素抵抗高度相关，因此了解调节脂肪细胞中CHREBP的机制可能会导致预防和治疗2型糖尿病的新型治疗方法。