IPA: Mechanisms that elicit weight loss with selective peptide agonism

IPA：通过选择性肽激动作用引起体重减轻的机制

• 批准号: BB/W000989/1
• 负责人: Simon Luckman
• 金额: $ 74.35万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW000989%2F1
• 关键词: IPA; Mechanisms; elicit; weight; loss

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.

我们目前生活在肥胖症的流行中，这对个人和整个社会的健康都有巨大的影响。因此，我们必须研究我们的身体在正常和肥胖条件下是如何调节脂肪质量的，以便我们可能提供新的途径来教育或治疗体重超标的人。大多数治疗肥胖症的方法包括减少我们的食物摄入量，要么是通过节食，要么是药物治疗，要么是手术。另一种选择是通过增加锻炼或改变我们“储存”的脂肪和“燃烧掉”的脂肪之间的平衡来增加我们消耗的能量。长期以来，我们的实验室一直对大脑如何控制体重感兴趣。特别是，我们之前已经证明，产生一种名为RFamide的信使的脑细胞可以相当显著地影响体重。一些RFamide减少食物摄入量，而另一些则增加能量消耗，或者两者兼而有之。最近，我们发现作用于RFamide受体的选择性药物可以减轻肥胖小鼠的体重，因为这些药物是在体内而不是大脑内给药的。非常重要的是，这些药物不会影响老鼠吃的食物的量。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具有这种效果。然而，我们不知道这是因为老鼠制造的脂肪更少还是燃烧的更多。我们也不知道这些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，我们将检查对不同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。我们将培育在大脑的特定细胞中表达特殊基因的小鼠。这些小鼠通常是健康的，但我们预测，如果给予高脂肪饮食，它们将变得非常肥胖，类似于今天发生在英国人身上的情况。通过使用这些小鼠，我们将能够准确地确定药物在哪里起作用。在未来，这将使我们和我们在制药行业的合作伙伴能够设计出治疗肥胖的新方法。