G protein-coupled receptors for energy metabolites as new therapeutic targets

In recent years, several G protein-coupled receptors (GPCRs) have been identified that are activated by energy substrates such as fatty acids and sucrose, or by metabolic intermediates such as acetate, lactate or ketone bodies.These carbohydrate or lipid metabolites, by activating specific GPCRs, function in a hormone-like fashion in addition to their role as carriers of energy.Metabolite receptors sense metabolic activity or levels of energy substrates and control the secretion of metabolic hormones or regulate the metabolic activity of particular cells.Synthetic ligands of the heterodimeric sweet receptor taste receptor type 1 member 2 (TAS1R2)–TAS1R3, which is a receptor for mono- and disaccharides, are used as artificial sweeteners but may have additional metabolic functions, as TAS1R2–TAS1R3 appears to be also involved in non-gustatory metabolic functions.The long-chain fatty acid receptors free fatty acid receptor 1 (FFA1; (also known as GPR40) and GPR120 (also known as omega-3 fatty acid receptor 1) mediate beneficial effects by promoting glucose-induced insulin secretion and by inhibiting inflammatory signalling in immune cells, respectively.The short-chain fatty acid receptors FFA2 (also known as GPR43) and FFA3 (also known as GPR41) appear to link the gut microbiota to metabolic and immune functions. Whether these receptors can be exploited therapeutically is currently not clear.Succinate receptor 1 (SUCNR1; also known as GPR91), which is activated by the citric acid cycle intermediate succinate (released by cells following cellular stress or hypoxia), is involved in the regulation of blood pressure, retinal angiogenesis and immune functions.Of the hydroxycarboxylic acid receptors, which are activated by ketone bodies or lactate, hydroxycarboxylic acid receptor 2 (HCA2) — which is also activated by nicotinic acid — in particular is of pharmacological interest as it mediates some anti-dyslipidaemic effects as well as anti-inflammatory effects, which can be used to reduce the progression of atherosclerosis and potentially other diseases.Several of these receptors have been tested as targets for drugs to treat particular metabolic diseases, and various synthetic ligands have been developed in recent years. Agonists of FFA1 and HCA2 are currently being tested in clinical trials.