Oxytocin pathways affecting metabolism

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等重大问题，这些疾病的治疗给NHS带来了巨大的压力。随着肥胖的发展，大脑开始抵抗来自身体的反馈信号，这些信号通常表明这个人超重了。因此，即使吃饱了，个人也会倾向于吃得过多。要逆转肥胖，就需要治疗绕过这种阻力；但是很难设计出既能进入大脑又没有副作用的药物。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，人们已经知道大脑释放催产素来控制分娩和母乳喂养。然而，大脑中释放的催产素可以调节社会关系，例如母亲和婴儿之间的关系。事实上，大脑中的催产素似乎确实会影响许多不同类型的行为。产生催产素的细胞数量少的人（普瑞德-威利综合症）是肥胖的，胃口很大。最近在肥胖动物模型中进行的实验表明，尽管动物对身体的反馈信号有抵抗力，但长期服用催产素会减少食物摄入，增加能量消耗。重要的是，在人类的研究中，催产素通过鼻内喷雾剂直接进入大脑，可以减少对食物的渴望，进食和体重。虽然这看起来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。我们从以前的肥胖治疗中吸取了教训，这些治疗被证明是危险的，因为有看不见的副作用。我们预测催产素是有效和安全的，因为它绕过身体的反馈信号，模仿我们通常在两餐之间经历的自然循环饱腹感信号。我们将提供证据，证明催产素细胞（神经元）的活性在不引起不良反应的情况下降低食欲，同时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途径介导的。大脑中有一小块区域叫做室旁核，里面有大量的催产素神经元，它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，还有其他种类的催产素神经元，所以我们需要确定我们研究的是正确的细胞。我们已经开发了转基因老鼠，我们可以看到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，并观察它们在大脑的其他地方建立联系。通过让不同的种群表达一种“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的区域的连接对动机行为有影响。因此，我们假设激活这种联系会自然地减少饥饿感（而不是通过引起厌恶反应，比如生病）。第二个投射到脑干，在那里控制肠道的信号被整合。在这里，我们认为催产素减缓了胃向肠道释放食物的速度。这种延迟排空会增加饱腹感，延长两餐之间的饱腹感。最后，第三个投影直接指向脊髓。在这里，催产素作用于外周组织的输出，包括脂肪库。我们储存多余能量的白色脂肪组织活动增加，导致脂肪分解。同样，一种叫做棕色脂肪的特殊组织的活动增加了能量消耗，从而燃烧了更多的卡路里。

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.