MRS Studies of Brain Mitochondrial Function in Metabolic Syndrome

这个项目的中心假设是线粒体功能的改变是一个关键 代谢综合征的决定因素。然而，尽管代谢综合征已经广泛地 以肌肉、肝脏、肾脏和胰腺为特征，人们对其如何影响大脑知之甚少 功能。了解代谢综合征对大脑影响的潜在重要性 两条交汇的证据线突出了它的作用。首先，最近的研究表明， 与包括阿尔茨海默氏症和颞叶癫痫在内的许多神经退行性疾病有关的大脑线粒体功能受损。其次，流行病学研究发现，在2型糖尿病患者中，神经退行性疾病的总发病率增加了几倍。严重胰岛素抵抗患者的大脑线粒体减少可能是这种易感性增加的一个因素。在项目3中，我们将利用我们最近的 无创成像脑线粒体代谢功能的MRS方法的发展，以评估在三组代谢综合征受试者中是否发生改变。这些人群是1)患有II型糖尿病的父母的胰岛素抵抗的后代，2)老年受试者和3)线粒体tRNA编码基因突变的患者。舒尔曼实验室最近的MRS研究表明，这三组人都改变了肌肉线粒体的新陈代谢。我们在这个项目中的总体假设是，这些受试者的大脑中存在与肌肉和肝脏相似的大脑线粒体新陈代谢的变化。该项目将为大脑提供第一个全面的代谢综合征研究，并可能为为什么患有代谢综合征的人患神经退行性疾病的风险增加提供新的见解。

The central hypothesis of this program project is that altered mitochondrial function is a key determinant of metabolic syndrome. However while metabolic syndrome has been extensively characterized in muscle, liver, kidney and pancreas, little is known about how it impacts brain function. The potential importance of understanding the impact of metabolic syndrome on brain function is highlighted by two converging lines of evidence. Firstly, recent studies have strongly implicated impaired brain mitochondrial function in a host of neurodegenerative diseases, including Alzheimer's and temporal lobe epilepsy. Secondly, epidemiological studies have found a several fold enhancement in the total incidence of neurodegenerative diseases in patients with type 2 Diabetes Metlitus. Reduced brain mitochondria in people with severe insulin resistance may be a factor in this increased susceptibility. In project 3 we will take advantage of our recent developments of MRS methods for non-invasively imaging brain mitochondrial metabolic function to assess whether it is altered in three groups of subjects with metabolic syndrome. These groups are 1) insulin resistant offspring of parents with Type II diabetes, 2) elderly subjects and 3) patients with an identified mutation in a gene coding for mitochondrial tRNA. Recent MRS studies by the Shulman laboratory have shown that all three groups have altered muscle mitochondrial metabolism. Our general hypothesis in this project is that there are similar alterations in brain mitochondrial metabolism in the brain of these subjects as in the muscle and liver. This project will )rovide the first comprehensive study of metabolic syndrome to brain, and may provide new insight nto why subjects with metabolic syndrome are at increased risk of neurodegenerative disease.