Paola Chiarugi

Deregulated metabolism is a well‐known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone‐like molecules by activating cell surface G‐protein‐coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis‐derived and β‐oxidation‐derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite‐sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.