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

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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.