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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，超过四分之一的英国成年人肥胖，导致糖尿病和心血管疾病的主要问题，这些疾病的治疗给NHS带来了巨大的压力。随着肥胖症的发展，大脑变得对来自身体的反馈信号具有抵抗力，这些反馈信号通常表明人超重。因此，即使吃饱了，个体也会倾向于吃得过多。为了扭转肥胖，需要绕过这种抵抗力的治疗;但是很难设计出可以进入大脑并且没有不良副作用的药物。许多商业和学术团体正在研究的一个目标是催产素系统。多年来，人们已经知道，催产素是从大脑中释放出来的，以控制分娩和母乳喂养。然而，大脑中释放的催产素可以调解社会联系，例如母亲和婴儿之间的联系。事实上，大脑中的催产素似乎确实影响了许多不同类型的行为。催产素产生细胞数量少的人（普拉德-威利综合征）肥胖，食欲旺盛。最近在肥胖动物模型中的实验表明，长期服用催产素会减少食物摄入量并增加能量消耗，即使动物对身体的反馈信号有抵抗力。重要的是，在人类的研究中，催产素通过鼻内喷雾直接进入大脑，可以减少对食物的渴望，进食和体重。虽然它看起来像是一种非常有前途的治疗方法，但人们对催产素如何带来这些有益效果知之甚少。从以前的肥胖治疗中吸取了教训，这些治疗由于不可见的副作用而被证明是危险的。我们预测催产素是有效和安全的，因为它绕过了身体的反馈信号，模仿了我们通常在两餐之间体验到的自然周期性饱腹感信号。我们将提供证据表明，活动的催产素细胞（神经元）降低食欲而不造成不良影响，而在同一时间增加能量消耗和脂肪分解。我们将证明催产素的这些作用是由大脑中不同的通路介导的，在大脑的一个小区域，称为室旁核，有一群催产素神经元，它们整合来自身体的信号，然后激活一些不同的输出，这些输出将直接或间接地影响体重。然而，还有其他的催产素神经元群体，所以我们需要确保我们正在研究正确的细胞。我们已经开发出转基因小鼠，我们可以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，并观察它们在大脑其他地方的连接。通过使不同的群体表达一种“设计受体”，我们可以在行为正常的小鼠中选择性地激活它们，从而确定室旁催产素神经元的重要性。这些神经元投射到大脑的不同部位，影响新陈代谢的不同方面。与一个叫做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会自然地减少饥饿（而不是通过引起厌恶反应，如疾病）。第二个投射到脑干，在那里控制肠道的信号被整合。在这里，我们相信催产素减缓了胃向肠道释放食物的速度。这种延迟排空增加了饱腹感，延长了两餐之间的饱腹感。最后，第三个投射直接到达脊髓。催产素作用于外周组织，包括脂肪库。我们储存多余能量的白色脂肪组织的活动增加，导致脂肪分解。同样，一种称为棕色脂肪的特殊组织的活动增加，会增加能量消耗，从而燃烧更多的卡路里。