Delineating the roles of GPR55 in cellular metabolism and energy homeostasis

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The G-protein coupled receptor (GPCR) superfamily play crucial roles in cell communication. As such, they mediate the effects of circulating hormones and other biologically active molecules across the blood-facing membranes of cells to regulate diverse cell/tissue processes including, for example, sensory perception, metabolism and satiety. Given their involvement in neurological disorders, inflammatory and metabolic diseases, diabetes and cardiac dysfunction they represent the largest and most successful class of "druggable" targets in the human body. However, despite the immense current interest in GPCR biology, the function of numerous members of this family remain poorly understood, but which may well represent important therapeutic targets for treatment of major public health issues, such as obesity, diabetes and cardiovascular disease. This project aims to explore links between a lipid sensing GPCR, called GPR55, and processes influencing adiposity, inflammation, cardiac function and response to insulin within key metabolic tissues, such as white fat, liver, skeletal muscle and heart. These tissues are major targets for insulin in the body and represent the principal sites where sugar (glucose) and fat are stored and metabolised in response to the hormone. GPR55 is stimulated by a circulating lipid called LPI, which we find improves the response of these metabolic tissues to insulin and also helps lower inflammatory drive in cells derived from them. Crucially, this LPI-mediated response is lost if cells are co-treated with a GPR55 inhibitor. Strikingly, we have discovered that animals deficient in this lipid sensor exhibit reduced tissue responsiveness to insulin, impaired metabolic capacity and a decline in cardiac performance. Metabolic capacity is crucially dependent upon mitochondria; structures within cells representing the cell's "energy generator". Significantly, animals lacking GPR55 show changes in mitochondrial biology consistent with a reduced ability to "burn" fat. In line with this, we find animals lacking GPR55 develop obesity and that inhibiting the receptor in cultured adipocytes (fat cells) induces proteins that help make more fat, which would augment the process of obesity. Precisely how GPR55 links to the molecular regulation of the above processes is currently unclear. The studies described in this application will utilise cells in culture from rodent and human origin as well as mouse tissues for laboratory-based analysis to help dissect out the role GPR55 plays not only with respect to insulin action and inflammation, but in control of tissue adiposity (fatness) and cardiac function. The project will also explore whether GPR55 activation helps mitigate the increase in fat gain, the loss in tissue sensitivity to insulin and cardiac dysfunction in mice fed a high fat calorie diet. Tissues taken from animals at the end of such studies will be processed for biochemical analysis and state-of-the-art whole cell/tissue protein profiling - an approach that will identify which proteins become up- or down-regulated in tissues of mice lacking GPR55 or in cells in which GPR55 has been activated/inhibited with selective drugs. This methodology will generate a wealth of information, potentially unveiling novel proteins that connect with GPR55 to regulate how insulin works or fat is stored or "burnt". Importantly, the large scale protein profiling may flag-up proteins that have not previously been linked to GPR55, but which may be central to the work of researchers in other fields thus providing an invaluable data resource to the scientific community. Collectively, our pilot studies indicate GPR55 may function as a novel metabolic regulator within tissues and suggest that understanding how it regulates insulin action, lipid metabolism and cardiac function may offer new pharmacological opportunities for treatment of metabolic disorders associated with conditions such as obesity and type II diabetes.