GPR103 has multi-tissue effects on health and metabolism

点击翻译按钮获取中文摘要

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.