Abstract
Fatty acids are metabolized and synthesized as energy substrates during biological responses. 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. 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. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. 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. 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. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.
Highlights
Free fatty acids (FFAs) AS DIETARY METABOLITES G protein-coupled receptors (GPCRs) FOR FFAs FFAR1/GPR40 GPR120/FFAR4 GPR43/FFAR2 GPR41/FFAR3 OTHER GPCRs FOR FFAs CONCLUSIONS
Maslowski et al [203] reported that FFAR2-deficient mice showed deteriorated inflammation in mouse models of arthritis, colitis, and asthma, while germfree wild-type mice showed correspondingly exacerbated inflammatory conditions. These results clearly show that FFAR2 mediates the beneficial effects of short-chain fatty acids (SCFAs), which are present in a high-fiber diet, on the immune system and inflammation
After colonization of germ-free mice with specific microbes, wild-type mice, but not FFAR3-deficient mice, showed increased peptide YY (PYY) levels. These results indicate that SCFA production by bacterial fermentation is essential for the activation of FFAR3 function and that PYY secretion of gut motility is important for SCFA absorption
Summary
Free 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 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 focus on the recent advances in our knowledge and understanding about FFARs
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