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Conclusion
Conflict of interest
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Acknowledgements
Introduction Free fatty acids (FFAs) are essential nutrients that contribute to various cellular functions. Several epidemiological and physiological studies have examined the beneficial or harmful effects of FFAs [1], [2]. FFAs exert biological effects through several signaling pathways; however, the precise mechanisms remain unclear. FFAs are associated with intracellular and nuclear proteins such as FA-binding proteins and peroxisome proliferator-activated receptors (PPARs) [3], [4]. Activation of G protein-coupled receptors (GPCRs) by FFAs has been predicted because some physiological functions of FFAs are difficult to describe. During the past decade, several FFA receptors (FFARs) have been identified. Ligand profiles of FFARs depend on the length of the carbon chain of FFAs. Thus, FFA2 and FFA3 receptors are activated by short-chain FFAs, whereas FFA1 and FFA4 are activated by medium- and long-chain FFAs. In contrast, GPR84 is activated by medium-chain FFAs but not by long carbon chains. Expression and functional studies of FFARs have shown that these receptors are strongly associated with energy metabolism (Table 1). Therefore, FFARs have received considerable attention as potential therapeutic targets for energy metabolism disorders such as obesity and type 2 diabetes. However, the ligand profiles of short-chain and medium- to long-chain FFA receptors are similar to each other, and the expression profiles of these receptors in pancreas, intestine, and immune BMS345541 hydrochloride australia partly overlap. Therefore, the development of selective ligands (Fig. 1) and gene knockout studies would be essential to reveal the precise physiological functions of these receptors. Particularly, in addition to the basic properties such as distribution, signaling pathways, and ligands, it is important to focus on how these receptors are orchestrated in the whole body and systemically contribute to the pathogenesis of disease, which in turn might provide novel insights into therapeutic options. This review summarizes the crucial and basic properties previously reported, as well as the recent advances in FFAR functions in relation to energy metabolism.
Short-chain FFAs (SCFAs) SCFAs consisting of chains less than 6 carbons have various physiological functions. Acetate (C2), propionate (C3), and butyrate (C4) are major products in the bacterial fermentation of dietary fiber with gut microbiota and are used as an energy source in epithelial cells of the intestinal tract and in the liver [5], [6]. SCFAs are therefore considered as endogenous ligands for SCFA receptors expressed in the intestines. In addition, the increase in the plasma levels of SCFAs from micromolar to millimolar levels activates the expression of SCFA receptors in leukocytes and sympathetic nerves.
Medium- to long-chain fatty acids Medium- to long-chain fatty acids impart a wide range of physiological effects. Medium-chain and long-chain fatty acids have 6–12 carbons and >12 carbons, respectively. As the energy source, these fatty acids are supplied primarily by food intake, biosynthesis, and lipolysis from adipose tissues. However, as unsaturated fatty acids such as linoleic acid, linolenic acid, and DHA that have more than 2 double bonds in the structures were not provided by biosynthesis in humans, we need to derive these macromolecules from food. Medium- to long-chain fatty acids are metabolized by β-oxidation and used as an energy source in various tissues. On the other hand, fatty acid receptors that are activated by these fatty acids provided the novel possibility of the biological functions of fatty acids for signaling molecules and the insight for the importance of dietary habits.
Medium- to long-chain fatty acid receptors
Conclusion