From a cell signaling perspective given the importance of ag

From a cell signaling perspective, given the importance of agonist-directed signaling and biased agonism, one goal of this research update was to review the known contributions of G protein-dependent versus β-arrestin-dependent signals toward promotion of beneficial functions that FFA4 facilitates. As described, many, but not all of the anti-inflammatory effects of FFA4 are modulated by β-arrestin-2 (Fig. 3); yet, other beneficial effects (e.g., adipocyte GLUT-4 translocation and glucose uptake) are Gαq/11-mediated, while still others were noted to putatively involve Gαi/o or even Gαs. From the viewpoint of stimulus-bias, and given the importance of FFA4 phosphorylation and β-arrestin recruitment to receptor function, drug discovery efforts must ensure that proper high-throughput assays are utilized in screening of MRS 2768 tetrasodium salt libraries to assess both Ca2+ mobilization, as has been historically performed for GPCRs, and also β-arrestin recruitment, as many are doing today.
Acknowledgments Portions of this work were supported fully or in part by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant [DK098730] and three Diabetes Action Research and Educational Foundation grants to N.H.M.
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 cells 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.