Oxytocin pathways affecting metabolism

影响新陈代谢的催产素途径

基本信息

批准号：
MR/P024017/1
负责人：
Simon Luckman
金额：
$ 56.77万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP024017%2F1
关键词：
Oxytocin pathways affecting metabolism

项目摘要

Currently over a quarter of UK adults are obese, leading to major problems with diabetes and cardiovascular disease, the treatment of which puts immense strain on the NHS. As obesity develops, the brain becomes resistant to feedback signals from the body which normally indicate that the person is overweight. As a consequence the individual will tend to overeat even when full. To reverse obesity, treatments will be required to bypass this resistance; but it is difficult to design drugs which can access the brain and that do not have unwanted side effects. One target being investigated by a number of commercial and academic groups is the oxytocin system. It has been known for many years that oxytocin is released from the brain to control child birth and breast feeding. However, oxytocin released within the brain can mediate social bonding, for example between a mother and her baby. It seems that oxytocin within the brain does, in fact, affect many different types of behaviour. Humans with low numbers of oxytocin-producing cells (Prader-Willi Syndrome) are obese and have powerful appetites. Recent experiments in obese animal models have shown that long-term administration of oxytocin decreases food intake and increases energy expenditure, even though the animals are resistant to the body's feedback signals. Importantly, studies in humans, where oxytocin accesses the brain directly via an intranasal spray, can reduce food cravings, eating and body weight. While it looks like a very promising treatment, little is known about how oxytocin brings about these beneficial effects. Lessons have been learned from previous obesity treatments that have proven dangerous because of unseen side effects. We predict that oxytocin is effective and safe because it bypasses the body's feedback signals and mimics the natural cyclical satiety signals that we normally experience in between meals. We will provide evidence that the activity of oxytocin cells (neurones) reduce appetite without causing adverse effects, while at the same time increasing energy expenditure and fat break down. We will demonstrate that these actions of oxytocin are mediated by distinct pathways in the brain.There is a population of oxytocin neurones in a small area of the brain, called the paraventricular nucleus, which integrate signals from the body and then activate a number of different outputs which will affect body weight either directly or indirectly. However, there are other populations of oxytocin neurone, so we need to be sure we are studying the correct cells. We have developed transgenic mice in which we can visualise and manipulate oxytocin neurones. Thus, we can record the electrical activity of these neurones and look to see where they make connections elsewhere in the brain. By making different populations express a "designer receptor", we can then activate them selectively in normally behaving mice, thus establishing the importance of the paraventricular oxytocin neurones. These neurones project to distinct parts of the brain to affect different aspects of metabolism. A connection with an area called the BNST has an effect on motivational behaviour. Thus, we hypothesise activating this connection will reduce hunger naturally (and not by causing an aversive response, such as sickness). A second projection goes to the brainstem, where signals controlling the gut are integrated. Acting here, we believe oxytocin slows down the rate at which the stomach releases food into the gut. This delayed emptying increases feelings of fullness and extends the period of satiety between meals. Finally, a third projection goes directly to the spinal cord. Here oxytocin acts on outputs to peripheral tissues, including fat depots. Increased activity in white adipose tissue, where we store excess energy, leads to a breakdown of fat. Likewise, higher activity in a specialised tissue, called brown adipose, increases energy expenditure, so that more calories are burned.

目前，四分之一的英国成年人肥胖，导致糖尿病和心血管疾病的重大问题，这种治疗对NHS造成了巨大的压力。随着肥胖的发展，大脑对身体的反馈信号具有抵抗力，通常表明该人超重。结果，即使在满满的情况下，个人也会倾向于暴饮暴食。为了逆转肥胖，将需要治疗绕过这种抗药性；但是，很难设计可以进入大脑并且没有不必要的副作用的药物。催产素系统是许多商业和学术组对一个目标进行调查的目标。多年来，催产素已从大脑释放出来，以控制儿童的出生和母乳喂养。但是，大脑中释放的催产素可以介导母亲和婴儿之间的社会联系。实际上，似乎大脑中的催产素确实会影响许多不同类型的行为。数量少的产生催产素细胞（Prader-Willi综合征）的人是肥胖的，并且食欲强大。肥胖动物模型的最新实验表明，即使动物对人体的反馈信号有抵抗力，催产素的长期给药会降低食物摄入并增加能量消耗。重要的是，在人类中，催产素直接通过鼻内喷雾进入大脑的研究可以减轻食物的渴望，饮食和体重。虽然这看起来像是一种非常有前途的治疗方法，但对催产素如何带来这些有益作用的方式知之甚少。由于看不见的副作用，从以前的肥胖治疗中学到了经验教训。我们预测催产素是有效且安全的，因为它绕开了人体的反馈信号，并模仿我们通常在两餐之间经历的自然周期性饱腹感信号。我们将提供证据表明，催产素细胞（神经元）的活性减少了食欲而不会引起不良影响，同时增加了能量消耗和脂肪破裂。我们将证明催产素的这些作用是由大脑中不同途径介导的。在大脑的一小部分中，有催产素神经元的群体，称为旁腔核核，这些核核核核核核核核核元素会直接或独立地影响体重。但是，还有其他种群的催产素神经元，因此我们需要确保我们正在研究正确的细胞。我们已经开发了转基因小鼠，可以在其中可视化和操纵催产素神经元。因此，我们可以记录这些神经元的电活动，并希望看到它们在大脑其他地方之间的连接在哪里。通过使不同的种群表达“设计师受体”，我们可以在正常行为的小鼠中选择性地激活它们，从而确立旁腔内催产素神经元的重要性。这些神经元投射到大脑的不同部分，以影响代谢的不同方面。与称为BNST的区域的联系对动机行为有影响。因此，我们假设激活这种联系将自然减少饥饿（而不是引起厌恶反应，例如疾病）。第二个投影将转移到脑干上，其中控制肠道的信号是集成的。在这里，我们认为催产素会减慢胃释放到肠道的速度。这延迟的空空会增加饱满感，并延长两餐之间的饱腹感。最后，第三个投影直接进入脊髓。这里的催产素作用于包括脂肪库在内的外周组织的输出。我们存储多余能量的白色脂肪组织的活性增加导致脂肪分解。同样，在称为棕色脂肪的专用组织中的较高活性会增加能量消耗，从而燃烧更多的卡路里。