妊娠期宫内高糖环境对子代肝脏线粒体MCAT影响及其诱发糖尿病的机制研究

Gestational intrauterine hyperglycemia is an important factor for offspring obesity, diabetes and other chronic diseases. In mitochondria, malonyl CoA-acyl carrier protein transacylase (MCAT), the key enzyme in glucose-fatty acid metabolism, can regulate pyruvate dehydrogenase (PDH) activity to affect insulin sensitivity. However, there is no report about the effects of gestational intrauterine environment on mitochondrial MCAT or PDH. In this study, we will examine the effects of intrauterine hyperglycemia on offspring liver mitochondrial MCAT and PDH expression and their functional changes in glucose-fatty acid metabolism. Then, we will use MCAT liver specific knockout mice and MCAT gene slicing technique in cells to determine the role of MCAT in glucose-fatty acid metabolism and insulin resistance. Finally, we will use the gene chip to validate the differences of MCAT and PDH to choose the key pathways and targets in glucose and fatty acid metabolism. Our study will explore the effects of gestational intrauterine hyperglycemia on offspring glucose and fatty acid metabolism and their potential mechanisms, and provide new targets for early diagnosis and prevention of diabetes.

妊娠期宫内高糖环境是子代发生肥胖、糖尿病及其他慢性疾病的一个重要决定因素。线粒体中调节糖脂代谢的关键酶丙二酰辅酶A酰基载体蛋白转酰酶（MCAT）可以通过影响丙酮酸脱氢酶（PDH）活性调节胰岛素敏感性，而妊娠环境对线粒体MCAT及PDH的影响目前研究甚少。本研究拟通过妊娠期糖尿病小鼠传代模型，研究宫内高糖环境对子代小鼠肝脏线粒体MCAT、PDH表达和功能的变化及其对糖脂代谢的影响。随后采用MCAT肝脏特异性敲除小鼠和体外细胞MCAT基因沉默技术，分析MCAT在糖脂代谢及胰岛素抵抗中的作用。最后通过基因芯片分析，对MCAT和PDH表达差异进行验证，筛选出糖脂代谢中的关键通路与靶分子。本研究有望阐明妊娠期宫内高糖环境对子代糖脂代谢的影响及其作用机制，为糖尿病的早期预警及干预提供新的靶点。

妊娠期宫内高糖环境是子代发生肥胖、糖尿病及其他慢性疾病的一个重要决定因素。线粒体中调节糖脂代谢的关键酶丙二酰辅酶A酰基载体蛋白转酰酶（MCAT）可以通过影响丙铜酸脱氢酶（PDH）活性调节胰岛素敏感性，而妊娠环境对线粒体MCAT及PDH的影响目前研究甚少。本研究通过妊娠期糖尿病小鼠传代模型，发现宫内高糖环境对子代小鼠肝脏线粒体MCAT、PDH表达和功能进行调节从而影响糖脂代谢。随后采用MCAT肝脏特异性敲除小鼠模型发现MCAT在糖脂代谢及胰岛素抵抗中发挥重要作用。最后通过基因芯片分析，对MCAT和PDH表达差异进行验证，筛选出糖脂代谢中的关键通路与靶分子。本项目首次研究宫内高糖环境影响子代肝脏MCAT功能从而影响其糖脂代谢，为糖尿病的早期预警及干预提供新的靶点。