GPR103 has multi-tissue effects on health and metabolism

GPR103 对健康和新陈代谢具有多组织影响

• 批准号: BB/J005509/1
• 负责人: Simon Luckman
• 金额: $ 53.74万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ005509%2F1
• 关键词: GPR103; multi; tissue; effects; health

We are experiencing an epidemic in the prevalence of metabolic diseases which are associated mainly with increasing obesity. As the body becomes obese there is an increase in the amount of lipid (fat and cholesterol) and glucose (sugar) circulating in the body, which can lead to diseases such as blocked arteries (increasing the chances of heart attacks or stroke) and diabetes (increasing the chances of kidney failure or blindness). Treating the diseases associated with obesity is close to bankrupting the NHS and, therefore, it is critical that we understand the development of these diseases to save money and promote healthy living. Our metabolism is controlled by different organs in a coordinated fashion. The pancreas produces hormones like insulin to control glucose uptake, while the liver can take up or produce more glucose depending on needs. Likewise, the fat in our bodies is actually stored as another organ: white adipose tissue. White adipose tissue around our abdomens and thighs, not only stores fat, but it too produces hormones. The coordination of these organs (pancreas, liver and adipose tissue), however, is ultimately governed by the brain. Few factors act in a coordinated manner on all of these organs in the body. However, recently, we have found a messenger, called QRFP, has major actions in the brain and other organs to increase food intake, circulating glucose and fat production. We will demonstrate that different types of receptors for QRFP mediate these different actions. We will produce mice which do not have the two types of receptor. Then we will produce a series of other genetically-modified mice in which we can manipulate just the cells in the body that produce QRFP. In this way, we will be able to switch the QRFP cells on and off, simply by giving the mice a drug. We can do this very briefly, or over a longer period to see the development of metabolic disorders. Instead, we can start with a mouse that has no QRFP and then genetically re-introduce QRFP into one organ at a time, to isolate its different effects. Finally, we will be able to use the mice to determine how QRFP-producing cells connect with other cell types. This work will validate QRFP as a key regulator of metabolism. As QRFP has many different effects on different organs, it may be an ideal target to develop drugs against its actions. A drug that can block QRFP would reduce food intake, make the body more sensitive to insulin so that glucose is controlled better, and reduce the amount of fat produced by adipose tissue. Doing this would lead to increasing health and wellbeing.

我们正在经历代谢疾病流行的流行病，这些疾病主要与肥胖症的增加有关。当身体变得肥胖时，体内循环的脂质（脂肪和胆固醇）和葡萄糖（糖）的量会增加，这会导致诸如动脉阻塞（增加心脏病发作或中风的机会）和糖尿病（增加肾衰竭或失明的机会）等疾病。治疗与肥胖相关的疾病接近于使NHS破产，因此，我们了解这些疾病的发展以节省资金并促进健康生活至关重要。我们的新陈代谢是由不同的器官以协调的方式控制的。胰腺产生胰岛素等激素来控制葡萄糖的摄取，而肝脏可以根据需要摄取或产生更多的葡萄糖。同样，我们体内的脂肪实际上是作为另一个器官储存的：白色脂肪组织。我们的腹部和大腿周围的白色脂肪组织，不仅储存脂肪，而且也产生激素。然而，这些器官（胰腺、肝脏和脂肪组织）的协调最终由大脑控制。很少有因素以协调的方式作用于体内的所有这些器官。然而，最近，我们发现了一种名为QRFP的信使，它在大脑和其他器官中具有增加食物摄入、循环葡萄糖和脂肪产生的主要作用。我们将证明，不同类型的受体QRFP介导这些不同的行动。我们将培育出没有这两种受体的小鼠。然后，我们将生产一系列其他的转基因小鼠，在这些小鼠中，我们可以操纵体内产生QRFP的细胞。通过这种方式，我们将能够打开和关闭QRFP细胞，只需给小鼠一种药物。我们可以很短的时间内观察，也可以在较长的时间内观察代谢紊乱的发展。相反，我们可以从没有QRFP的小鼠开始，然后一次将QRFP基因重新引入一个器官，以隔离其不同的影响。最后，我们将能够使用小鼠来确定产生QRFP的细胞如何与其他细胞类型连接。这项工作将验证QRFP作为代谢的关键调节剂。由于QRFP对不同器官有许多不同的影响，因此它可能是开发针对其作用的药物的理想目标。一种可以阻断QRFP的药物将减少食物摄入，使身体对胰岛素更敏感，从而更好地控制葡萄糖，并减少脂肪组织产生的脂肪量。这样做将导致增加健康和福祉。

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.

Physiological Roles of GPR10 and PrRP Signaling.

• DOI: 10.3389/fendo.2013.00020
• 发表时间: 2013-01-01
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Dodd, Garron T;Luckman, Simon M
• 通讯作者: Luckman, Simon M