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Targeting the aspartic protease BACE1 for inhibition in order to increase hypothalamic leptin sensitivity and reverse obesity.

针对天冬氨酸蛋白酶 BACE1 进行抑制，以增加下丘脑瘦素敏感性并逆转肥胖。

基本信息

批准号：
MR/K003291/1
负责人：
Michael Ashford
金额：
$ 52.71万
依托单位：
University of Dundee
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK003291%2F1
关键词：
Targeting aspartic protease BACE1 inhibition

项目摘要

Chronic obesity is currently at epidemic levels in the UK and many other countries worldwide and is having a major adverse impact on our society. It is estimated that more 25% of the adult population are obese and around two thirds are either overweight or obese. Worryingly over the last 20 years there has been a ~3 fold increase in the number of children and adolescents who are obese or overweight. This trend is alarming, as chronic obesity is associated with increased risk of a number of diseases such as diabetes, cardiovascular disease, Alzheimer's and a number of cancers. It is clear that our society is on a trajectory that will see significant increases in the proportion of individuals entering or in old age with severe chronic health issues. This places an enormous burden on the NHS and society generally, which is likely to worsen over the next 10-20 years if effective actions are not taken soon.The hormone, leptin, plays an important role in the maintenance of long term body weight and fat levels in animals and humans, It acts in the brain, in an area called the hypothalamus, to decrease feeding and increase energy expenditure. However, leptin's effects on appetite and energy expenditure are diminished in aged and obese individuals, despite increased circulating levels of the hormone. This phenomenon is known as leptin resistance and is thought to be due to reduced transport of leptin into the brain and/or a loss of the ability of leptin to alter the function of cells in the hypothalamus. Thus in non-obese individuals leptin alters the amount of certain neurotransmitters within neurons, their release onto nearby cells and their actions on these cells. These effects are lost or diminished through diet-induced obesity in both humans and animal models of obesity. Presently there are few effective drug treatments for obesity and none that overcome leptin resistance in the hypothalamus. The enzyme, BACE1 cuts a larger protein known as amyloid precursor protein resulting in smaller protein fragments, some of which are thought to be toxic and responsible for the pathology associated with Alzheimer's Disease (AD). Indeed, excessive activity of BACE1 in the brain is thought to be the primary driver for the neurodegeneration and cognitive dysfunction associated with AD. The amount and activity of BACE1 increases with age and following pathological stresses such as hypoxia, oxidative stress (e.g. free radicals) and physical brain injury, thus increasing the risk of AD. Features common to AD and to diabetes and obesity are the loss of function of important metabolic hormones such as insulin and leptin and the reduced ability of cells to take up and use glucose. Consequently, we hypothesised that BACE1 plays an important role that connects cell stresses (metabolic, oxidative and inflammatory) with glucose and fat metabolism. To date our work has shown that removing or decreasing BACE1 in mice causes them to be lean, resistant to weight (fat) gain on a high fat (calorie) diet and to improve their ability to deal with increased amounts of glucose in the blood (as occurs after a meal). In other words, these mice appear resistant to obesity and diabetes normally induced by chronic excess caloric intake. In a pilot study we show that by reducing the amount of BACE1, leptin is more effective in the hypothalamus and remains so even when animals become obese (i.e obesity is reversible by increasing the amount of leptin in the blood). This information suggests that reducing BACE1 prevents or reverses leptin resistance. Importantly our recent experiments show that giving obese mice (which are resistant to endogenous leptin) a drug that inhibits BACE1 causes significant weight loss. We now wish to confirm and extend these preliminary findings by studying a larger number of animals made obese by high fat diet and to try to define what has changed in the hypothalamus to circumvent leptin resistance.

慢性肥胖症目前在英国和世界上许多其他国家处于流行水平，对我们的社会产生重大不利影响。据估计，超过25%的成年人肥胖，约三分之二的人超重或肥胖。令人担忧的是，在过去的20年里，肥胖或超重的儿童和青少年人数增加了3倍。这一趋势令人担忧，因为慢性肥胖与糖尿病、心血管疾病、阿尔茨海默氏症和一些癌症等多种疾病的风险增加有关。很明显，我们的社会正处于一个轨道上，进入或进入老年的严重慢性健康问题的个人比例将显着增加。这给NHS和整个社会带来了巨大的负担，如果不尽快采取有效措施，这种情况可能在未来10-20年内恶化。激素，瘦素，在动物和人类的长期体重和脂肪水平的维持中起着重要作用，它作用于大脑，在一个称为下丘脑的区域，减少进食和增加能量消耗。然而，瘦素对食欲和能量消耗的影响在老年和肥胖个体中减少，尽管激素的循环水平增加。这种现象被称为瘦素抵抗，并且被认为是由于瘦素进入大脑的运输减少和/或瘦素改变下丘脑细胞功能的能力丧失。因此，在非肥胖个体中，瘦素改变了神经元内某些神经递质的数量，它们向附近细胞的释放以及它们对这些细胞的作用。在人类和肥胖动物模型中，这些作用通过饮食诱导的肥胖而丧失或减弱。目前，很少有有效的药物治疗肥胖症，没有克服下丘脑中的瘦素抵抗。BACE 1酶切割一种称为淀粉样前体蛋白的较大蛋白质，产生较小的蛋白质片段，其中一些被认为是有毒的，并负责与阿尔茨海默病（AD）相关的病理学。事实上，大脑中BACE 1的过度活性被认为是与AD相关的神经变性和认知功能障碍的主要驱动因素。BACE 1的量和活性随着年龄和病理应激（例如缺氧、氧化应激（例如自由基）和物理性脑损伤）而增加，从而增加AD的风险。AD以及糖尿病和肥胖症的共同特征是重要代谢激素如胰岛素和瘦素的功能丧失以及细胞摄取和使用葡萄糖的能力降低。因此，我们假设BACE 1在连接细胞应激（代谢、氧化和炎症）与葡萄糖和脂肪代谢方面起着重要作用。到目前为止，我们的工作已经表明，去除或减少小鼠中的BACE 1会使它们变瘦，抵抗高脂肪（卡路里）饮食中的体重（脂肪）增加，并提高它们处理血液中葡萄糖增加的能力（如餐后发生的）。换句话说，这些小鼠似乎对通常由慢性过量热量摄入引起的肥胖和糖尿病具有抵抗力。在一项初步研究中，我们表明，通过减少BACE 1的量，瘦素在下丘脑中更有效，即使动物变得肥胖（即通过增加血液中瘦素的量，肥胖是可逆的）。这一信息表明，减少BACE 1可以预防或逆转瘦素抵抗。重要的是，我们最近的实验表明，给肥胖小鼠（对内源性瘦素有抵抗力）一种抑制BACE 1的药物会导致显着的体重减轻。现在，我们希望通过研究大量高脂饮食导致肥胖的动物来证实和扩展这些初步发现，并试图确定下丘脑发生了什么变化，以避免瘦素抵抗。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes.

DOI：
10.1007/s00125-014-3269-x
发表时间：
2014-08
期刊：
DIABETOLOGIA
影响因子：
8.2
作者：
Hamilton, D. Lee;Findlay, John A.;Montagut, Gemma;Meakin, Paul J.;Bestow, Dawn;Jalicy, Susan M.;Ashford, Michael L. J.
通讯作者：
Ashford, Michael L. J.

Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation.

DOI：
10.1038/srep31159
发表时间：
2016-08-08
期刊：
Scientific reports
影响因子：
4.6
作者：
McGuire VA;Ruiz-Zorrilla Diez T;Emmerich CH;Strickson S;Ritorto MS;Sutavani RV;Weiβ A;Houslay KF;Knebel A;Meakin PJ;Phair IR;Ashford ML;Trost M;Arthur JS
通讯作者：
Arthur JS

Conditional knock out of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in adipocytes improves metabolic health and reduces adipocyte inflammation

有条件地敲除脂肪细胞中的 β 位点淀粉样蛋白前体蛋白裂解酶 1 (BACE1) 可改善代谢健康并减少脂肪细胞炎症