Perinatal Nutrition in Development of Insulin Resistance

围产期营养在胰岛素抵抗发展中的作用

• 批准号: 7083203
• 负责人: COLLEEN MARIE CRONIGER
• 金额: $ 28.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7083203
• 关键词: adipose tissue; binding sites; bioenergetics; developmental nutrition; diabetes mellitus genetics; dietary lipid; esterification; free fatty acids; gene deletion mutation; gene expression; genetic promoter element; genetically modified animals; glucose metabolism; hypoglycemic agents; insulin sensitivity /resistance; kidney metabolism; laboratory mouse; lactation; liver metabolism; mammary gland; milk; mother /embryo /fetus nutrition; nutrition related tag; pathologic process; perinatal; peroxisome proliferator activated receptor; phosphoenolpyruvate carboxylase; thiazoles; tissue /cell culture; triglycerides

DESCRIPTION (provided by applicant): The increase in obesity and the development of type 2 diabetes in childhood is of great concern. The acute elevation of free fatty acids (FFA) levels, as occurs in obesity, is controlled by the triglyceride/FFA cycle. As much as 60% of the FFA released by the adipose tissue during fasting is re-esterified back to triglyceride within the adipose tissue and liver through a pathway called glyceroneogenesis. We have studied the role of the triglyceride/fatty acid cycle in the development of insulin resistance, using a mouse model with a deletion of the PPAR binding site in the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) gene promoter (PPARE-/- mice). This mutation results in ablation of expression of the PEPCK-C gene in the white adipose tissue and brown adipose tissue as well as in the mammary gland. In 5-week-old virgin PPARE-/- mice, the mammary gland has fewer terminal end buds (TEB) and less branching compared to wild type mice. The PPARE-/- females are fertile and able to produce milk for their young; however, the triglyceride content of the milk from the PPARE-/- mothers contains 40% less triglyceride than the wild type mice. The reduced triglyceride content in the milk has metabolic consequences. Pups from PPARE-/- mothers exhibit insulin resistance as early as 9-days after birth and this insulin resistance persists into adulthood. We hypothesize that the alteration of the triglyceride/fatty acid cycle through the deletion of the PEPCK-C gene expression in the adipose tissues and mammary gland results in 1)an increase of FFA levels in the blood, which ultimately causes insulin resistance and 2) in alteration of triglyceride content of the milk during lactation patterns the pup for insulin resistance. Using both the PPARE-/- mice and mouse mammary epithelial cell lines we propose to 1) Determine the role the triglyceride/fatty acid cycle through the regulation of the PEPCK-C gene in the patterning of the mouse for the development of insulin resistance, 2) investigate the in vivo functions of the PEPCK-C gene in the mammary gland and 3) determine the action of thiazolidinediones (TZD) in the alteration of the triglyceride/fatty acid cycle in the liver, adipose and mammary gland through regulation of PEPCK-C gene transcription at the PPARE binding site in the promoter of PEPCK-C gene. Understanding the regulation of PEPCK-C and defining its role in the mammary gland is critical to our understanding of the development of glucose homeostasis and diabetes.

描述（由申请人提供）：儿童肥胖的增加和2型糖尿病的发展是非常值得关注的。游离脂肪酸（FFA）水平的急性升高，如肥胖，是由甘油三酯/FFA循环控制的。禁食期间脂肪组织释放的FFA中有多达60%通过甘油生成途径在脂肪组织和肝脏内重新酯化回甘油三酯。我们研究了甘油三酯/脂肪酸循环在胰岛素抵抗发展中的作用，使用了一种缺失PPAR结合位点的小鼠模型，该模型在细胞质形式的磷酸烯醇丙酮酸羧酸激酶（PEPCK-C）基因启动子（PPARE-/-小鼠）中缺失。这种突变导致PEPCK-C基因在白色脂肪组织和棕色脂肪组织以及乳腺中的表达减少。在5周大的pare -/-小鼠中，与野生型小鼠相比，乳腺的终末芽（TEB）和分支较少。PPARE-/-雌性具有生育能力，能够为幼崽产奶；然而，来自PPARE-/-母鼠的乳汁中的甘油三酯含量比野生型小鼠低40%。牛奶中甘油三酯含量的降低对新陈代谢有影响。来自PPARE-/-母鼠的幼崽在出生后9天就表现出胰岛素抵抗，这种胰岛素抵抗会持续到成年。我们假设，脂肪组织和乳腺中PEPCK-C基因表达的缺失导致甘油三酯/脂肪酸循环的改变，导致1)血液中FFA水平的增加，最终导致胰岛素抵抗；2)哺乳期间乳汁中甘油三酯含量的改变，导致幼犬胰岛素抵抗。利用PPARE-/-小鼠和小鼠乳腺上皮细胞系，我们提出：1)通过调控PEPCK-C基因确定甘油三酯/脂肪酸循环在小鼠胰岛素抵抗发展模式中的作用；2)研究PEPCK-C基因在乳腺中的体内功能；3)确定噻唑烷二酮（TZD）在肝脏甘油三酯/脂肪酸循环改变中的作用。通过调控PEPCK-C基因启动子中PPARE结合位点的转录来促进脂肪和乳腺的生长。了解PEPCK-C的调控并确定其在乳腺中的作用对于我们理解葡萄糖稳态和糖尿病的发展至关重要。