A thermogenic circuit that maintains sensitivity to leptin in obesity

维持肥胖患者对瘦素敏感性的生热回路

• 批准号: BB/L021129/1
• 负责人: Simon Luckman
• 金额: $ 53.95万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL021129%2F1
• 关键词: thermogenic; circuit; maintains; sensitivity; leptin

We are experiencing an epidemic in the prevalence of obesity; a disease which develops after the body's protective systems become overwhelmed in an environment which is full of sugary and fatty foods. Normally when we put weight on, our fat tissues release a hormone called leptin, that travels to the brain to help us to reduce eating, but also to increase the amount of energy we burn off by a process called thermogenesis (literally, heat production). One of the reasons we find it difficult to lose the extra weight is because the parts of the brain that control eating, become resistant to the effects of leptin, so it no longer works. We have learned a lot about the part of the brain controlling eating, because we have identified the types of nerve cells there which possess the capability to respond to leptin (i.e. those that have receptors for the hormone). Importantly, a different part of the brain controls the thermogenic response to leptin, and the cells here do not become resistant to leptin. This makes them of great interest to scientists and doctors wishing to find way of reducing the obesity problem. Unfortunately, until now we did not know what types of cells these were.In our preliminary work leading up to this project, we have now identified three different cell types which all appear to play a role in thermogenesis. However, only one of them has leptin receptors. The cells that are directly sensitive to leptin contain a signaling chemical called PrRP. Our hypothesis is that the PrRP-containing nerves control the other cell types and also the messages from the brain to the organs that actually cause thermogenesis. We have bred different types of mice which will allow us to study the different cell types very carefully. We will be able to see how they respond to leptin, how they make connections, and how they communicate with each other. Perhaps most excitingly, for the first time ever, we can switch on or off the different nerves selectively, just by giving the mice a harmless drug. Thus, we can switch on the nerves to drive thermogenesis or switch the nerves off to stop them responding to leptin.A complete understanding of the different types of nerves will allow the selective targeting of either the nerves themselves or their connections with the organs that control thermogenesis. This knowledge will help the discovery of drugs which, one day, could help prevent the development of obesity.

我们正在经历一种肥胖症的流行；这种疾病是在人体的保护系统在充斥着含糖和脂肪的食物的环境中不堪重负后发展起来的。正常情况下，当我们体重增加时，我们的脂肪组织会释放一种名为瘦素的荷尔蒙，这种荷尔蒙会进入大脑，帮助我们减少进食，但也会增加我们通过生热作用(字面意思是热量产生)消耗的能量。我们发现很难减掉多余体重的原因之一是，大脑中控制饮食的部分对瘦素的影响产生了抵抗力，因此它不再起作用。我们对大脑控制进食的部分已经了解了很多，因为我们已经确定了那里有能力对瘦素做出反应的神经细胞类型(即那些有激素受体的神经细胞)。重要的是，大脑的不同部分控制着对瘦素的生热反应，这里的细胞不会对瘦素产生抵抗力。这使得科学家和医生对它们产生了极大的兴趣，他们希望找到减少肥胖问题的方法。不幸的是，到目前为止，我们还不知道这些细胞是什么类型的。在这个项目之前的初步工作中，我们现在已经确定了三种不同的细胞类型，它们似乎都在产热过程中发挥了作用。然而，它们中只有一个有瘦素受体。对瘦素直接敏感的细胞含有一种称为PrRP的信号化学物质。我们的假设是，含有PrRP的神经控制着其他类型的细胞，也控制着从大脑到器官的信息，这些信息实际上导致了产热。我们培育了不同类型的小鼠，这将使我们能够非常仔细地研究不同类型的细胞。我们将能够看到它们对瘦素的反应，它们如何建立联系，以及它们如何相互沟通。也许最令人兴奋的是，有史以来第一次，我们可以有选择地打开或关闭不同的神经，只需给老鼠一种无害的药物。因此，我们可以打开神经来驱动产热，或者关闭神经来阻止它们对瘦素的反应。完全了解不同类型的神经将允许选择性地瞄准神经本身或它们与控制产热的器官的连接。这些知识将有助于发现药物，这些药物有朝一日可能有助于预防肥胖的发展。

项目成果

The hypothalamic RFamide, QRFP, increases feeding and locomotor activity: The role of Gpr103 and orexin receptors.

• DOI: 10.1371/journal.pone.0275604
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Cook, Chris;Nunn, Nicolas;Worth, Amy A.;Bechtold, David A.;Suter, Todd;Gackeheimer, Susan;Foltz, Lisa;Emmerson, Paul J.;Statnick, Michael A.;Luckman, Simon M.
• 通讯作者: Luckman, Simon M.

Sequential Exposure to Obesogenic Factors in Females Rats: From Physiological Changes to Lipid Metabolism in Liver and Mesenteric Adipose Tissue.

• DOI: 10.1038/srep46194
• 发表时间: 2017-04-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Novelle MG;Vázquez MJ;Peinado JR;Martinello KD;López M;Luckman SM;Tena-Sempere M;Malagón MM;Nogueiras R;Diéguez C
• 通讯作者: Diéguez C

The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.

• DOI: 10.1016/j.cmet.2014.07.022
• 发表时间: 2014-10-07
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Dodd GT;Worth AA;Nunn N;Korpal AK;Bechtold DA;Allison MB;Myers MG Jr;Statnick MA;Luckman SM
• 通讯作者: Luckman SM