IPA: Mechanisms that elicit weight loss with selective peptide agonism

我们目前生活在一个肥胖的流行病中，这对个人和整个社会都有巨大的健康后果。因此，我们有必要研究我们的身体在正常和肥胖的情况下是如何调节脂肪量的，这样我们就可以提供新的途径来教育或治疗体重过重的人。大多数治疗肥胖的方法包括通过节食、药物或手术来减少我们吃的食物量。另一种选择是通过增加锻炼或改变我们“储存”的脂肪和“消耗”的脂肪之间的平衡来增加我们消耗的能量。我们的实验室长期以来一直对大脑如何控制体重感兴趣。特别是，我们之前已经表明，产生一类称为RFamides的信使的脑细胞可以非常显著地影响体重。一些rfamide减少食物摄入，而另一些则增加能量消耗，或者两者兼而有之。最近，我们发现，选择性药物作用于RFamides受体，当药物进入体内而不是进入大脑时，可以减轻肥胖小鼠的体重。非常重要的是，这些药物不会影响老鼠吃的食物量。相反，它们似乎会影响脂肪在体内的处理方式。这是令人兴奋的，因为目前还没有安全的治疗方法有这种效果。然而，我们不知道这是因为老鼠产生的脂肪更少还是燃烧掉的更多。我们也不知道药物是否必须进入大脑才能发挥作用，或者它们是否直接作用于其他器官，如肝脏或脂肪库。为了回答这些问题，我们将研究对不同的RFamide受体具有不同亲和力的药物，并测量它们对脂肪平衡的作用。我们将培育在大脑特定细胞中表达特殊基因的老鼠。这些老鼠通常都很健康，但我们预测，如果给它们高脂肪饮食，它们会变得非常胖，就像今天英国人的情况一样。通过使用这些老鼠，我们将能够准确地指出药物在哪里起作用。在未来，这将使我们和我们在制药行业的合作者能够设计出治疗肥胖的新方法。

We are currently living in an obesity epidemic which has huge health consequences for individuals and for the whole of society. Therefore, it is imperative that we investigate how our body regulates fat mass under normal and obese conditions, so that we might provide new avenues to educate or treat people suffering with excess body weight. Most treatments for obesity involve decreasing the amount of food we eat, either through dieting, pharmaceutical drugs or surgery. An alternative would be to increase the amount of energy we expend either by increasing exercise or by changing the balance between the fat we "store away" and the amount we "burn off." Our laboratories have had a long-standing interest in how the brain controls body weight. In particular, we have shown previously that brain cells, which produce a class of messenger called RFamides, can affect body weight quite dramatically. Some RFamides reduce food intake, while others increase energy expenditure, or do both. Recently, we have discovered that selective drugs which act on the receptors for RFamides can reduce body weight in obese mice, when the drugs are administered into the body, rather than into the brain. Very importantly, the drugs do not affect the amount of food the mice eat. Instead, they appear to affect the way fat is handled in the body. This is exciting because currently there are no safe treatments which have this effect. However, we do not know whether this is because the mice make less fat or burn more off. Nor do we know if the drugs have to get into the brain to have their effect, or whether they act directly on other organs, such as the liver or fat depots. To answer these questions, we will examine drugs which have different affinities for different RFamide receptors and measure their action on fat balance. We will breed mice which express special genes in specific cells of the brain. These mice are normally healthy, but we predict that they will become very fat if given a high-fat diet, similar with what is happening to people in the UK today. By using these mice, we will be able to pinpoint exactly where the drugs are having their action. In the future, this will allow us and our collaborators within the pharmaceutical industry to devise new treatments for obesity.