G protein-coupled receptors (GPCRs) are seven transmembrane receptors that activate the heterotrimeric G protein. However, some FFA-induced physiological responses cannot be attributed to these sensors and thus other mechanisms involving plasma membrane receptors may be expected to mediate the biological processes of FFAs. As the physiological sensors of FFAs, members of the intracellular or nuclear lipid-binding protein families, such as fatty acid binding proteins (FABPs) and peroxisome proliferator activated receptors (PPARs), are known as functional receptors that regulate many physiological and pathophysiological processes ( 47, 93). In addition to their function as an energy source, FFAs show critical functions such as receptor signaling, gene expression, and regulation of systemic fuel energy homeostasis under various physiological conditions ( 30, 106, 212). We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.įree fatty acids (FFAs) are important energy sources for most body tissues and are classified according to their aliphatic tail length short-chain fatty acids (SCFAs) have fewer than 6 carbon atoms, medium-chain fatty acids (MCFAs) have 6–12 carbons, and long-chain fatty acids (LCFAs) have 12 or more carbons. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized.
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Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Fatty acids are metabolized and synthesized as energy substrates during biological responses.
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