Defining signal selection from the free fatty acid receptor FFA4; implications for physiological functions

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G protein-coupled receptors (GPCRs) are a large family of proteins, located predominantly at the surface of cells, that act as sensors of changes in the external environment of cells and tissues of the body. Although members of the GPCR family are already the most successful class of drug targets, relatively few of them have yet been targeted in this way. We believe this is due to a lack of understanding of the basic underpinning biology of many GPCRs, and a paucity of pharmacological tool compounds and appropriate animal models to test their in vivo function in both normal physiology and in the context of disease. Although traditionally viewed as being designed to detect and instruct cells to respond to alterations in the concentration of various hormones and neurotransmitters, in recent times it has become clear that a substantial number of GPCRs are designed to respond directly to alterations in metabolites that are produced by digestion of foodstuffs and, in so doing, they alert organs of the body to co-ordinate responses to either a dearth or a surplus of nutrients. Given that many diseases that are currently rising to epidemic proportions, e.g. diabetes and obesity, develop from a 'Western lifestyle' of intake of a marked excess of highly calorific foods and a lack of exercise, then mimicking or blocking the effects of the GPCRs for such metabolic products may have beneficial effects. Indeed, for the receptor we plan to study in detail, which is called free fatty acid receptor 4 (FFA4), understanding of its ability when activated to regulate blood glucose levels, and to increase the effectiveness of the hormone insulin, has resulted in ongoing efforts by the pharmaceutical industry to assess if activation of FFA4 might be a novel approach to treat type II diabetes.Like many other GPCRs, FFA4 is expressed by range of types of cells in the body, leading to suggestions that either activating or blocking this receptor might also have benefits in other conditions. It is clear that FFA4 can instruct cells to respond by controlling a number of different signalling pathways and in the proposed studies we plan to unravel this complexity and to understand which signals are predominant in different types of cells and tissues and how this determines the outcome of activating FFA4. We will do this in a number of ways. One of the most exciting and important will be to utilise cells and tissues from mice, that in our current studies on this receptor that BBSRC have funded, we have genetically engineered to express a form of FFA4 that can only interact with so called G proteins and not with arrestins. Arrestins are a key set of signalling proteins that interact strongly with activated FFA4. Studies that compare functions of FFA4 in cells and tissues from normal and arrestin-interaction deficient mice will provide this information, and this will be examined in tissues that range from different types of fat cells, to cells of the immune system. These have been selected because of the roles FFA4 has been suggested to play in areas that range from fat cell development and inflammation, to how resistance develops to drugs that are used to shrink cancers in chemotherapy. In parallel with these large, overarching objectives we also plan to develop and utilise chemicals that block the actions of FFA4 that are much improved on those currently available, map in detail the expression pattern of FFA4 and employ cells we have developed from current BBSRC funding that have been 'genome-edited' to eliminate specific subsets of signalling pathways to allow us to assess if different types of molecule that activate FFA4 can selectively control the signalling potential of FFA4. By the end of the proposed studies FFA4 will no longer be a poorly studied GPCR and we will be in position to state with some confidence if regulating this receptor might be a means to treat 'Western lifestyle' diseases beyond diabetes.