GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation

G蛋白偶联受体(GPCRs)是一个非常大的细胞表面蛋白家族，对细胞和组织如何控制其功能是不可或缺的。正因为如此，某些GPCR是许多用于治疗疾病的药物的靶标。近年来，一些GPCR对脂肪酸等营养物质浓度的变化做出反应，这一点也变得明显。虽然最初令人惊讶，但这是有道理的，因为细胞需要能够随着食物和营养供应的变化而改变其功能。其中一个GPCR被指定为GPR120。由于GPR120能够对一组名为omega-3多不饱和脂肪酸的脂肪酸做出反应，这些脂肪酸在我们被鼓励食用的油性鱼类中含量较高，因为这些脂肪酸对健康有许多好处，因此人们对是否能识别出能够激活GPR120的合成化学物质产生了极大的兴趣，如果是这样的话，从长远来看，可能会提供新药的基础。GPR120由体内许多组织表达，包括作为重要炎症介质的巨噬细胞，以及胰岛素荷尔蒙的来源胰腺细胞和白色脂肪细胞。近年来，人们已经清楚地认识到，“炎症”是糖尿病等慢性疾病以及其他“衰老”疾病发展的重要因素。这进一步提高了人们对操纵GPR120活性可能是治疗糖尿病和相关疾病的有用的新方法的兴趣。尽管非常令人兴奋，但到目前为止，许多研究表明GPR120在这一健康和疾病领域是一个很好的靶点，因为刺激GPR120的脂肪酸类型也激活了其他受体，并具有许多与该受体无关的其他作用。此外，由于omega-3脂肪酸也被身体转化为其他介质，因此GPR120的一些功能实际上可能并不是以这种方式产生的。我们在本申请中提出的工作旨在分解和全面定义GPR120的功能。在过去的几个月里，我们开发并表征了已知的唯一一组合成化学配体，它们在GPR120和足够低的浓度下选择性地作用，我们可以肯定它们的作用确实需要激活GPR120。我们将利用这些来评估GPR120在包括巨噬细胞、脂肪细胞和胰腺细胞在内的细胞中的激活如何控制它们的功能、它们的激素和其他介质的产生以及它们与其他类型的细胞的相互作用。GPCRs可以以多种方式对不同的配体作出反应，有时还会以不同的方式作出反应(这称为偏向)。一个共同的特征是，通过在特定的氨基酸上添加磷酸基团，受体被迅速修饰。这种磷酸化既可以限制受体功能，也可以启动一系列新的信号。我们也希望为GPR120探索这一点。我们已经准确地确定了GPR120中哪些氨基酸被修饰，并制作了一种不会发生这种情况的受体版本。我们希望评估这一点的影响，并为此我们将产生GPR120的改变版本取代正常形式的小鼠。然后，这些动物将提供细胞和组织，以评估GPR120的哪些生理功能需要磷酸化，哪些不需要。与此相配合，我们还将制造抗体，只有当GPR120被磷酸化时才能识别它，并将使用这些抗体来确定在不同条件下受体被激活的程度，例如当小鼠喂食高脂肪食物时。有趣的是，有一种GPR120的变体只在人类中发现，我们也定义了它的作用。我们研究的最终目标是确定是否有充分的理由投入大量、时间和金钱来开发以GPR120为治疗策略的合成药物。

G protein-coupled receptors (GPCRs) are a very large family of cell surface proteins integral to how cells and tissues control their function. Because of this certain GPCRs are the targets for many medicines used to treat disease. In recent times it has also become clear that a number of GPCRs respond to alterations in concentration of nutrients such as fatty acids. Although initially surprising this makes sense as cells need to be able to alter their function as food and nutrient availability changes. One of these GPCRs is designated GPR120. Because of the capacity of GPR120 to respond to a group of fatty acids called omega-3 polyunsaturated fatty acids, which are present in high levels in the types of oily fish that we are encouraged to eat because these fatty acids have many health benefits, there has been great interest in whether synthetic chemicals could be identified that would activate GPR120 and if so might, in the longer term, provide the basis of novel medicines. GPR120 is expressed by a number of tissues in the body, including macrophages, that are important mediators of inflammation, and both pancreatic cells, the source of the hormone insulin, and white fat cells. In recent years it has become clear that 'inflammation' is an important contributor to the development of chronic diseases such as diabetes as well as other diseases of 'aging'. This has further raised interest in the possibility that manipulating the activity of GPR120 might be a useful, novel approach to treat diabetes and related conditions. Although very exciting, to date many of the studies implicating GPR120 as a good target in this area of health and disease have been indirect, because the type of fatty acids that stimulate GPR120 also activate other receptors and have many other effects that are not related to this receptor. Furthermore, because the omega-3 fatty acids are also converted into other mediators by the body it is possible that some of the functions suggested for GPR120 are not actually produced this way. The work we propose in this application is designed to unravel and define fully the functions of GPR120. In the last few months we have developed and characterised the only known group of synthetic chemical ligands that act selectively at GPR120 and at sufficiently low concentrations that we can be sure their effects do require activation of GPR120. We will use these to assess how activation of GPR120 in cells including macrophages, adipocytes and pancreatic cells controls their function, their production of hormones and other mediators and their interactions with other cell types. GPCRs can respond to different ligands in multiple and sometimes in distinct ways (this is termed bias). A common feature is that the receptor is rapidly modified by the addition of phosphate groups to specific amino acids. Such phosphorylation can either limit receptor function or initiate a panoply of new signals. We wish to also explore this for GPR120. We have determined exactly which amino acids in GPR120 become modified and made a version of the receptor in which this cannot happen. We wish to assess the implications of this and to do so we will generate mice in which this altered version of GPR120 replaces the normal form. These animals will then provide cells and tissues to assess which physiological functions of GPR120 require phosphorylation and which do not. In concert with this we will also make antibodies that only identify GPR120 when it is phosphorylated and will use these to determine the extent to which the receptor is activated in different conditions, for example when mice are fed a high fat diet. Interestingly, there is a variant form of GPR120 that is only found in humans and we also define its role.The ultimate objective of our studies is to define if there is a strong case to be made in investing large amounts and time and money in developing synthetic medicines that target GPR120 as a therapeutic strategy.