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Review

Nutritional Signaling via Free Fatty Acid Receptors

by
Junki Miyamoto
1,
Sae Hasegawa
1,
Mayu Kasubuchi
1,
Atsuhiko Ichimura
2,
Akira Nakajima
1 and
Ikuo Kimura
1,*
1
Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-0057, Japan
2
Department of Biological Chemistry, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606-8501, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2016, 17(4), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040450
Submission received: 28 January 2016 / Revised: 7 March 2016 / Accepted: 17 March 2016 / Published: 25 March 2016
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
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Abstract

:
Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism.

Graphical Abstract

1. Introduction

Although diet is the most important source of daily nutrients, excess food intake leads to metabolic diseases, such as type 2 diabetes (T2D) and obesity. In recent years, obesity is one of the most critical health problems worldwide [1,2]. In the past decades, it has become increasingly apparent that all macronutrients, including carbohydrates, proteins and lipids, play an important role in the regulation of energy metabolism. Obesity develops as a result of a prolonged imbalance between energy expenditure and intake, which influences various metabolite- and hormone-related pathways [3]. Excessive food intake along with insufficient exercise and genetic susceptibility is considered a risk factor for obesity. Recent studies also suggest that the intestinal environment, particularly changes in gut microbiota composition, is closely linked to obesity and metabolic disorders [4,5,6]. One role of gut microbiota is to exchange free fatty acids (FFAs) derived from dietary fat for other FFAs as gut microbial metabolites that are key factors in energy metabolism.
FFAs are not only an essential energy source, but also function as signaling molecules that regulate various cellular processes and physiological functions according to carbon chain length. Short chain fatty acids (SCFAs) have no more than six carbons; medium chain fatty acids (MCFAs) have from 6–12 carbons; and long chain fatty acids (LCFAs) have greater than 12 carbons. Humans are unable to generate linoleic acid C18:2 (ω-6) and α-linolenic acid C18:3 (ω-3), because humans cannot synthesize the ω-6 or ω-3 double bond. Therefore, these fatty acids must be obtained from the diet. Humans can elongate and desaturate linoleic and α-linolenic acids to longer chain products, with variable rates of efficiency. MC- and LCFAs are metabolized by β-oxidation and are provided in tissues as an energy source. Dietary fibers have had interest in them owing to their beneficial metabolic effects on glucose homeostasis, food intake, insulin sensitivity and body weight [7,8]. SCFAs, such as acetate, propionate and butyrate, are produced by gut microbial fermentation of dietary fibers [9]. Gut microbiota affect host nutrient acquisition and energy regulation and can influence the development of obesity and diabetes [10]. Dietary fiber intake reduces the development of various diseases, such as inflammatory and metabolic disorders [11,12]. Therefore, SCFAs have been proposed to play a key role in the prevention and treatment of inflammatory and metabolic disorders [13,14,15]; for instance, butyrate derived from fibers improved insulin sensitivity and increased energy expenditure in a mouse model of diet-induced obesity [16].
FFA receptors (FFARs) are expressed in various tissues and influence many important metabolic functions that maintain energy homeostasis. Several orphan G protein-coupled receptors (GPCRs) have been identified as FFARs; SCFAs can activate GPR41/FFAR3 and GPR43/FFAR2, while MC- and LCFAs can activate GPR40/FFAR1 and GPR120/FFAR4 (Figure 1) [17,18,19,20,21,22,23]. These FFARs have the potential as new drug targets for metabolic diseases, such as T2D and obesity.

2. GPR40/FFAR1

GPR40 is a receptor for MCFAs and LCFAs and is reported to bind with Gq protein. GPR40 activation increases [Ca2+]i and activates the extracellular signal-regulated kinases (ERK1/2) signaling cascade. Gq protein is a heterotrimeric G protein subunit that activates phospholipase C (PLC) and then, intracellular Ca2+ release. On the other hand, it also increases cyclic (c)AMP levels via a Gs-coupled pathway [18,24]. MCFAs and LCFAs activate GPR40 at micromolar concentrations; docosahexaenoic acid (DHA) C22:6 (ω-3) and eicosapentaenoic acid (EPA) C20:5 (ω-3) are the most potent agonist of GPR40 (Table 1). Interestingly, GPR40 activation by saturated FAs depends on carbon chain length, with palmitic acid (C16) identified as potent ligands with high affinity for GPR40. GPR40 is abundantly expressed in pancreatic insulin-producing β cells and the intestine. LCFAs promote glucose-stimulated insulin secretion (GSIS) in pancreatic β cells, and the specific and acute effects of FFAs were mitigated by the loss of GPR40 function [19]. Acute and chronic effects of FFAs on insulin secretion have been investigated using Gpr40-deficient and pancreatic β cell-specific Gpr40 transgenic (TG) mice [25]; the chronic effects of LCFAs on GSIS were attenuated in the Gpr40-deficient mice, whereas GPR40 overexpression in pancreatic β cells prevented and improved insulin sensitivity in high fat diet (HFD)-induced obese mice [26]. Furthermore, acute and chronic effects of palmitic acid on insulin sensitivity exerted in part via GPR40 have been reported [27]. The downregulation of GPR40 mRNA by exendin-4 suppressed c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) cascade, blocking palmitic acid-induced apoptosis in pancreatic β cells [27], while glucose and FFAs in the pancreas have been shown to regulate GPR40 protein level [28].
GPR40 expression has been identified in the intestine, immune cells, taste buds and cells of the central nervous system [28,30,31,32,33,34]. Intestinal L and K cells, which produce incretin hormones, such as glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP), as well as cholecystokinin (CCK)-producing I cells all express GPR40. Hence, LCFAs directly activate GPR40 and enhance GSIS not only by direct stimulation of insulin secretion from pancreatic β cells, but also indirectly via upregulation of GLP-1, GIP and CCK in the intestine [35,36]. In addition, in Caco-2 cells, as a human intestinal epithelial cell line, GPR40 signaling induced by a gut microbial metabolite of linoleic acid restored intestinal epithelial barrier impairments [37]. GPR40 is also expressed in bovine neutrophils [38]. The selective GPR40 agonist GW9508 can modulate bovine neutrophil responses, such as ERK1/2 phosphorylation, superoxide production, CD11b expression and matrix metalloproteinase-9 release, in an [Ca2+]i-dependent manner. In taste buds, GPR40 plays a critical role in the taste response to nutritional sensing of LCFAs [39]; the receptor is primarily expressed on the back of the tongue, including on the circumvallate and foliate papillae [32]. Although further studies are needed to clarify the function of GPR40 in taste buds, these findings suggest that GPR40 has a key role in the perception of a lipid taste. GPR40 is also widely expressed in the central nervous system, including in neurons of the cerebral cortex, hippocampus, amygdala, hypothalamus, cerebellum and spinal cord [34]. Activation of GPR40 in neuroblastoma cells induced the phosphorylation of cAMP response element-binding protein (CREB) and ERK1/2; the former may influence the secretion of brain-derived neurotrophic factor (BDNF), which plays an important role in activity-dependent regulation of synaptic structure and function [40]. TAK-875, a potent and selective small-molecule agonist of GPR40, is useful for the development of the treatment for T2D by Takeda [41].

3. GPR120/FFAR4

GPR120 is a receptor for MC- and LCFAs that stimulates GLP-1 secretion from L cells in the colon [42] and is activated by various ω-3 or ω-6 polyunsaturated fatty acids, including docosahexaenoic acid (DHA) C22:6 (ω-3) and eicosapentaenoic acid C20:5 (ω-3), at micromolar concentrations. However, GPR120 is strongly activated by α-linolenic acid C18:3 (ω-3) (Table 1). Although the ligands’ affinity is similar to those of GPR40, the two receptors share only 10% amino acid homology. LCFAs increased [Ca2+]i, but exerted no effects on cAMP production in human or mouse GPR120-expressing cells, indicating that GPR120 is coupled with the Gq protein family, but not with the Gi/o or Gs protein families [43]. In addition, GPR120 activates ERK1/2 and phosphoinositide 3-kinase (PI3K), although the underlying mechanisms remain unclear [44].
GPR120 is widely expressed in many tissues and cell types, such as the intestine, pancreas, adipocytes and immune cells. This suggests that GPR120 has varied roles in energy regulation and immunological homeostasis. GPR120 activation by DHA had anti-inflammatory effects in macrophages [45] associated with the suppression of Toll-like receptor signaling via the β-arrestin-2 and with the inhibition of transforming growth factor-β-activated kinase 1, which is involved in pro-inflammatory tumor necrosis factor (TNF)-α signaling. Thus, GPR120 is an ω-3 FFA receptor that improves insulin resistance and anti-diabetic effects by suppressing tissue inflammation mediated by macrophages. Moreover, stimulation of FFAs induced GLP-1 and CCK secretion in mouse enteroendocrine STC-1 cells, as a murine enteroendocrine cell line, [43,46], while Gpr120 knockdown abolished FFA-induced effects on incretin secretion and [Ca2+]i levels [47]. The effect of FFAs on the plasma levels of GLP-1 and insulin were examined by the administration of FFAs into the mouse colon [42]. The lipid accumulation during the adipogenesis in 3T3-L1 cells, as a murine preadipocyte cell line, induced GPR120 expression [48], and Gpr120 knockdown in 3T3-L1 cells and the embryonic fibroblasts in Gpr120 deficient mice inhibited the adipogenic gene expressions and prevented lipid accumulation. These findings indicate that GPR120 plays an important role in the differentiation and maturation of adipocytes. In humans, GPR120 dysfunction leads to obesity, resulting in glucose intolerance and fatty liver accompanied by decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis [49]. Mutation from R (arginine) to H (histidine) at 270 amino acid sequences lacked the ability of GPR120 activation via LCFA and was significantly associated with obesity. These results provide insight into the contribution of LCFAs, which are often proposed as dietary supplements, to metabolism. Thus, GPR120 agonists could be useful for the improvement of insulin sensitivity for the treatment of T2D and other human insulin resistance [50].

4. GPR41/FFAR3

GPR41 is an SCFA receptor coupled with Gi/o, whose ligands include acetate (C2), propionate (C3) and butyrate (C4) [17,21]; and its ligand affinity is “propionate > butyrate > acetate” (Table 1). Recent studies have demonstrated that SCFAs produced by microbial fermentation act as signaling molecules via SCFA receptors, such as GPR41 and GPR43. Hence, gut microbiota play key roles in host physiological and pathological effects through these receptors. GPR41, which is expressed in adipose tissue, intestine and the peripheral nervous system, mediates systemic energy production by SCFAs, specifically by regulating intestinal gluconeogenesis and sympathetic activity. GPR41 expression in intestinal L cells that secrete GLP-1 and peptide YY (PYY) suggests its involvement in energy homeostasis [51]; indeed, PYY secretion from these cells is regulated by GPR41 signaling activated by gut microbiota-derived SCFAs [52]. Moreover, in primary cultured endocrine cells derived from Gpr41-deficient mice, Secretion of PYY and GLP-1 was reduced [53,54].
GPR41 is also abundantly expressed in the sympathetic nervous system (SNS); propionate promoted increasing energy expenditure and heart rate through GPR41 [54], effects that were not exhibited by Gpr41-deficient mice. Propionate is thought to control energy balance by directly regulating GPR41-mediated sympathetic activation. Under fasting conditions, β-hydroxybutyrate, which is a ketone body produced in the liver, decreased SNS activity by antagonizing GPR41, thereby reducing energy expenditure. Both SCFAs and ketone bodies reflect the nutrient status of an organism; these monocarboxylic metabolites control energy balance by directly regulating GPR41-mediated sympathetic activation. [54]. Thus, GPR41 acts as a nutritional sensor to regulate SNS activity and maintain energy balance in the body. GPR41 also enhances insulin sensitivity through the gut–brain neural circuit, which involves activation of peripheral nerve GPR41 by SCFAs produced by gut microbiota from dietary fibers [55]. GPR41 is expressed in mouse and human pancreatic β cells, as well as MIN6 cells, as a murine pancreatic β cell line, and EndoC-βH1 cells, as a human pancreatic β cell line, suggesting that it directly regulates insulin secretion [56]. Hence, SCFAs exhibit beneficial effects on the host metabolism via GPR41 that is exerted via the peripheral nervous system and hormone secretion in the gut.

5. GPR43/FFAR2

GPR43 is also identified as an SCFA receptor that can be activated by acetate (C2), propionate (C3) and butyrate (C4) [17,21]; and its ligand affinity is “acetate = propionate > butyrate” (Table 1). GPR43 is a Gi/o- and Gq-dual-coupled receptor that is expressed in enteroendocrine cells, such as L cells. PYY-expressing L cells in the colon were found to be immunoreactive for GPR43, while 5-hydroxytryptamine (serotonin)-positive mast cells [57]. PYY is an anorectic peptide that inhibits upper gastrointestinal tract motility and is released into the blood in response to SCFAs [58], an effect that may be mediated by activated GPR43. Additionally, GPR43 activation by SCFAs also promotes GLP-1 secretion in both colonic primary cultures and STC-1 cells [53,59]. In Gpr43-deficient mice, GLP-1 secretion by SCFAs reduced both in vitro and in vivo, and they have improved glucose tolerance [60]. GPR43 is also more highly expressed in the white adipose tissue of obese as compared to normal mice [60]; these investigators also reported that SCFAs inhibited lipolysis in a dose-dependent manner in 3T3-L1-derived adipocytes. These effects were dependent on GPR43 using Gpr43-deficient mice [61]. Moreover, obesity was induced in Gpr43-deficient mice by high fat diet and normal chow; however, adipose-specific Gpr43 TG mice were lean for each diet. GPR43 activation promotes energy expenditure and permitted the preferential usage of fat through suppression of fat accumulation by inhibition of adipose tissue-specific insulin signaling. Furthermore, these strains did not show each phenotype in the germ-free mice or antibiotic-treated mice. Thus, gut microbiota are the most important source of GPR43 agonists, and GPR43 activation is closely linked to the metabolites by gut microbiota. These results showed that SCFAs as ligands for GPR43 were dependent on the presence of gut microbiota and that GPR43 regulates adipose-insulin signaling by sensing gut microbial SCFAs; thereby, these studies clearly indicated the importance of SCFAs produced by gut microbiota and their receptors [62]. This implies that the GPR43-insulin pathway is an important physiological mechanism in which metabolites are used to maintain the balance of energy in the body [63,64]. GPR43 is also expressed in pancreatic β cells and regulates insulin secretion via Ca2+ flux through a Gq-coupled pathway [53]. Thus, GPR43 inhibits fat accumulation in adipose tissue, promotes GLP-1 secretion in the colon and directly regulates insulin secretion in the pancreas, thereby promoting systemic insulin sensitivity. Based on these findings, GPR43 agonists may be useful for the treatment of T2D.
Many studies have investigated the role of GPR43 in regulating inflammatory responses. Stimulation of GPR43 by acetate inhibited colitis and inflammation; conversely, Gpr43-deficient mice showed a severe inflammatory response in colitis, arthritis and asthma, which may be related to an increase in the recruitment of immune cells [65]. On the other hand, Gpr43-deficient mice showed a decreased survival rate comparison with healthy mice, despite the reduction of macrophage recruitment, colonic tissue inflammation and damage in an acute colitis model [66]. This duality in the action of SCFAs, that is, anti-inflammatory and neutrophil recruitment, is a key to understanding how SCFAs and GPR43 regulate inflammation and is consistent with the roles of human monocytes and peripheral blood mononuclear cells in the inflammatory response [67]. The oral administration of SCFAs protected T-cell-transfer colitis in a GPR43-dependent manner by regulating the size and function of the colonic pool of regulatory T-cells [68]. Finally, it has been suggested that prebiotic feeding can modulate inflammatory responses in colitis, obesity, diabetes and leukemia in rodent models [69]. It can be supposed that SCFAs are produced by the fermentation of gut microbes, which may show their anti-inflammatory effects in a GPR43-dependent manner, although additional studies are needed to investigate this possibility. GLPG0974 is an orally-available small GPR43 inhibitor, and was developed by Galapagos. This antagonist might have potential for the treatment of inflammatory bowel disease (NCT01829321).

6. Other GPCRs

Whereas LCFAs and SCFAs derived from the diet act as signaling molecules through GPCRs, GPR119 (a receptor for fatty acid amides and monoacylglycerol) and GPR84 (a receptor for MCFAs) also have physiological functions as nutritional receptors.
GPR119 is predominantly expressed in human and mouse enteroendocrine and pancreatic β cells. Oleoylethanolamide is an endogenous ligand for GPR119 and a peripherally-acting agent that reduces food intake and body weight gain in rat feeding models [70]. In addition, ligands, such as 2-monoacylglycerols, 2-oleoylglycerol, 2-palmitoylglycerol and 2-linoleoylglycerol, can activate GPR119 (Table 2) [71,72,73]. Thus, metabolic disorders can potentially be treated by inducing GPR119 activation and stimulating both GLP-1 and insulin secretion. GPR119 induces incretins, such as GLP-1 and GIP, in enteroendocrine cells [74]. In pancreatic β cells, GPR119 was shown to induce GSIS via cAMP production, suggesting that the receptor functions through activation of Gαs [75]. GPR119-mediated insulin secretion from the pancreas is glucose dependent, whereas GPR119-mediated GLP-1 secretion from enteroendocrine cells is thought to be glucose independent [76].
GPR84 is an MCFA receptor that is strongly activated by undecanoic acid (C11) and lauric acid (C12) (Table 3) [77]. GPR84 is associated with the pertussis toxin-sensitive Gi/o pathway and is mainly expressed in bone marrow and to a lesser degree in peripheral leukocytes and lungs [77,78]. GPR84 is highly expressed in monocytes and neutrophils upon lipopolysaccharide stimulation. Additionally, RAW264.7 cells, a mouse monocyte/macrophage cell line, produce the IL-12 p40 subunit upon MCFA stimulation [77]. Inducing and maintaining T helper (Th)1 response is a critical role of cell-mediated immunity, while inhibiting Th2 response is important for antibody-mediated immunity [79]. Gpr84-deficient mice exhibited an enhanced Th2 response, reflecting increased Th2 cytokine production [80]. Moreover, GPR84 was upregulated in a 3T3-L1 adipogenesis model and in the adipose tissue of obese patients and mice fed a HFD [80]. GPR84 in adipose tissue aggravates the pathogenesis of obesity and T2D via TNF-α released by infiltrating macrophages. Thus, GPR84 plays a pivotal role in metabolism and immune responses and may mediate crosstalk between immune cells and non-immune cells, such as adipocytes.

7. Conclusions

Host metabolic and immunological disorders have been linked to diet and gut microbiota composition. Many researchers have reported that FFARs are expressed in various tissues and cells as nutritional sensors and regulate both metabolic and inflammatory responses (Figure 1). In the future, FFAR signaling in diverse metabolic processes will provide new insights for nutritional science and drug discovery. Since the development of metabolic disorders, such as obesity and T2D, is caused by inflammation, the anti-inflammatory effects of FFARs are expected to be an important therapeutic target for the treatment of these diseases. It is well established that gut microbiota composition closely influences host energy metabolism and inflammatory responses; the discovery of FFARs, including GPR41, GPR43, GPR40, GPR84, GPR119 and GPR120, as receptors for gut microbial metabolites provides a molecular link that can explain these interactions. In conclusion, although further investigation of the relationship between FFARs and health is needed to clarify the underlying mechanisms, it might have an important role in the treatment of inflammatory and metabolic disorders and the development of therapeutic drugs.

Acknowledgments

While collecting the material for compiling this review, the authors received financial support by The Naito foundation Research Grant.

Author Contributions

Junki Miyamoto and Ikuo Kimura wrote the manuscript, and collaborate in figure management and technical editing of the manuscript; all authors critically revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kahn, S.E.; Hull, R.L.; Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006, 444, 840–846. [Google Scholar] [CrossRef] [PubMed]
  2. Sanz, Y.; Santacruz, A.; Gauffin, P. Gut microbiota in obesity and metabolic disorders. Proc. Nutr. Soc. 2010, 69, 434–441. [Google Scholar] [CrossRef] [PubMed]
  3. Greenwood, H.C.; Bloom, S.R.; Murphy, K.G. Peptides and their potential role in the treatment of diabetes and obesity. Rev. Diabet. Stud. 2011, 8, 355–368. [Google Scholar] [CrossRef] [PubMed]
  4. Greiner, T.; Bäckhed, F. Effects of the gut microbiota on obesity and glucose homeostasis. Trends Endocrinol. Metab. 2011, 22, 117–123. [Google Scholar] [CrossRef] [PubMed]
  5. Kau, A.L.; Ahern, P.P.; Griffin, N.W.; Goodman, A.L.; Gordon, J.I. Human nutrition, the gut microbiome and the immune system. Nature 2011, 474, 327–336. [Google Scholar] [CrossRef] [PubMed]
  6. Khan, M.T.; Nieuwdorp, M.; Bäckhed, F. Microbial modulation of insulin sensitivity. Cell Metab. 2014, 20, 753–760. [Google Scholar] [CrossRef] [PubMed]
  7. Delzenne, N.M.; Cani, P.D. A place for dietary fibre in the management of the metabolic syndrome. Curr. Opin. Clin. Nutr. Metab. Care 2005, 8, 636–640. [Google Scholar] [CrossRef] [PubMed]
  8. Delzenne, N.M.; Neyrinck, A.M.; Bäckhed, F.; Cani, P.D. Targeting gut microbiota in obesity: Effects of prebiotics and probiotics. Nat. Rev. Endocrinol. 2011, 7, 639–646. [Google Scholar] [CrossRef] [PubMed]
  9. Flint, H.J.; Bayer, E.A.; Rincon, M.T.; Lamed, R.; White, B.A. Polysaccharide utilization by gut bacteria: Potential for new insights from genomic analysis. Nat. Rev. Endocrinol. 2008, 6, 121–131. [Google Scholar] [CrossRef] [PubMed]
  10. Tarantino, G. Gut microbiome, obesity-related comorbidities, and low-grade chronic inflammation. J. Clin. Endocrinol. Metab. 2014, 99, 2343–2346. [Google Scholar] [CrossRef] [PubMed]
  11. Galisteo, M.; Duarte, J.; Zarzuelo, A. Effects of dietary fibers on disturbances clustered in the metabolic syndrome. J. Nutr. Biochem. 2008, 19, 71–84. [Google Scholar] [CrossRef] [PubMed]
  12. Den Besten, G.; van Eunen, K.; Groen, A.K.; Venema, K.; Reijngoud, D.J.; Bakker, B.M. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 2013, 54, 2325–2340. [Google Scholar] [CrossRef] [PubMed]
  13. Donohoe, D.R.; Garge, N.; Zhang, X.; Sun, W.; O’Connell, T.M.; Bunger, M.K.; Bultman, S.J. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011, 13, 517–526. [Google Scholar] [CrossRef] [PubMed]
  14. Harig, J.M.; Soergel, K.H.; Komorowski, R.A.; Wood, C.M. Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 1989, 320, 23–28. [Google Scholar] [CrossRef] [PubMed]
  15. Fukuda, S.; Toh, H.; Hase, K.; Oshima, K.; Nakanishi, Y.; Yoshimura, K.; Tobe, T.; Clarke, J.M.; Topping, D.L.; Suzuki, T.; et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011, 469, 543–547. [Google Scholar] [CrossRef] [PubMed]
  16. Gao, Z.; Yin, J.; Zhang, J.; Ward, R.E.; Martin, R.J.; Lefevre, M.; Cefalu, W.T.; Ye, J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009, 58, 1509–1517. [Google Scholar] [CrossRef] [PubMed]
  17. Brown, A.J.; Goldsworthy, S.M.; Barnes, A.A.; Eilert, M.M.; Tcheang, L.; Daniels, D.; Muir, A.I.; Wigglesworth, M.J.; Kinghorn, I.; Fraser, N.J.; et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 2003, 278, 11312–11319. [Google Scholar] [CrossRef] [PubMed]
  18. Briscoe, C.P.; Tadayyon, M.; Andrews, J.L.; Benson, W.G.; Chambers, J.K.; Eilert, M.M.; Ellis, C.; Elshourbagy, N.A.; Goetz, A.S.; Minnick, D.T.; et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 2003, 278, 11303–11311. [Google Scholar] [CrossRef] [PubMed]
  19. Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.; Fukusumi, S.; Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 2003, 422, 173–176. [Google Scholar] [CrossRef] [PubMed]
  20. Kotarsky, K.; Nilsson, N.E.; Flodgren, E.; Owman, C.; Olde, B. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem. Biophys. Res. Commun. 2003, 301, 406–410. [Google Scholar] [CrossRef]
  21. Le Poul, E.; Loison, C.; Struyf, S.; Springael, J.Y.; Lannoy, V.; Decobecq, M.E.; Brezillon, S.; Dupriez, V.; Vassart, G.; van Damme, J.; et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 2003, 278, 25481–25489. [Google Scholar] [CrossRef] [PubMed]
  22. Nilsson, N.E.; Kotarsky, K.; Owman, C.; Olde, B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 2003, 303, 1047–1052. [Google Scholar] [CrossRef]
  23. Hara, T.; Kimura, I.; Inoue, D.; Ichimura, A.; Hirasawa, A. Free fatty acid receptors and their role in regulation of energy metabolism. Rev. Physiol. Biochem. Pharmacol. 2013, 164, 77–116. [Google Scholar] [PubMed]
  24. Welters, H.J.; Diakogiannaki, E.; Mordue, J.M.; Tadayyon, M.; Smith, S.A.; Morgan, N.G. Differential protective effects of palmitoleic acid and cAMP on caspase activation and cell viability in pancreatic β-cells exposed to palmitate. Apoptosis 2006, 11, 1231–1238. [Google Scholar] [CrossRef] [PubMed]
  25. Steneberg, P.; Rubins, N.; Bartoov-Shifman, R.; Walker, M.D.; Edlund, H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 2005, 1, 245–258. [Google Scholar] [CrossRef] [PubMed]
  26. Nagasumi, K.; Esaki, R.; Iwachidow, K.; Yasuhara, Y.; Ogi, K.; Tanaka, H.; Nakata, M.; Yano, T.; Shimakawa, K.; Taketomi, S.; et al. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes 2009, 58, 1067–1076. [Google Scholar] [CrossRef] [PubMed]
  27. Kristinsson, H.; Smith, D.M.; Bergsten, P.; Sargsyan, E. FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion. Endocrinology 2013, 154, 4078–4088. [Google Scholar] [CrossRef] [PubMed]
  28. Sykaras, A.G.; Demenis, C.; Case, R.M.; McLaughlin, J.T.; Smith, C.P. Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS ONE 2012, 7, e42373. [Google Scholar] [CrossRef] [PubMed]
  29. Offermanns, S. Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 407–434. [Google Scholar] [CrossRef] [PubMed]
  30. Edfalk, S.; Steneberg, P.; Edlund, H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 2008, 57, 2280–2287. [Google Scholar] [CrossRef] [PubMed]
  31. Hirasawa, A.; Hara, T.; Katsuma, S.; Adachi, T.; Tsujimoto, G. Free fatty acid receptors and drug discovery. Biol. Pharm. Bull. 2008, 31, 1847–1851. [Google Scholar] [CrossRef] [PubMed]
  32. Cartoni, C.; Yasumatsu, K.; Ohkuri, T.; Shigemura, N.; Yoshida, R.; Godinot, N.; le Coutre, J.; Ninomiya, Y.; Damak, S. Taste preference for fatty acids is mediated by GPR40 and GPR120. J. Neurosci. 2010, 30, 8376–8382. [Google Scholar] [CrossRef] [PubMed]
  33. Liou, A.P.; Lu, X.; Sei, Y.; Zhao, X.; Pechhold, S.; Carrero, R.J.; Raybould, H.E.; Wank, S. The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 2011, 140, 903–912. [Google Scholar] [CrossRef] [PubMed]
  34. Ma, D.; Tao, B.; Warashina, S.; Kotani, S.; Lu, L.; Kaplamadzhiev, D.B.; Mori, Y.; Tonchev, A.B.; Yamashima, T. Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci. Res. 2007, 58, 394–401. [Google Scholar] [CrossRef] [PubMed]
  35. Hara, T.; Ichimura, A.; Hirasawa, A. Therapeutic role and ligands of medium- to long-chain fatty acid receptors. Front. Endocrinol. Lausanne 2014, 5, 83. [Google Scholar] [CrossRef] [PubMed]
  36. Tomita, T.; Hosoda, K.; Fujikura, J.; Inagaki, N.; Nakao, K. The G-Protein-Coupled Long-Chain Fatty Acid Receptor GPR40 and Glucose Metabolism. Front. Endocrinol. Lausanne 2014, 5, 152. [Google Scholar] [CrossRef] [PubMed]
  37. Miyamoto, J.; Mizukure, T.; Park, S.B.; Kishino, S.; Kimura, I.; Hirano, K.; Bergamo, P.; Rossi, M.; Suzuki, T.; Arita, M.; et al. A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40-MEK-ERK pathway. J. Biol. Chem. 2015, 290, 2902–2918. [Google Scholar] [CrossRef] [PubMed]
  38. Hidalgo, M.A.; Nahuelpan, C.; Manosalva, C.; Jara, E.; Carretta, M.D.; Conejeros, I.; Loaiza, A.; Chihuailaf, R.; Burgos, R.A. Oleic acid induces intracellular calcium mobilization, MAPK phosphorylation, superoxide production and granule release in bovine neutrophils. Biochem. Biophys. Res. Commun. 2011, 409, 280–286. [Google Scholar] [CrossRef] [PubMed]
  39. Yonezawa, T.; Kurata, R.; Yoshida, K.; Murayama, M.A.; Cui, X.; Hasegawa, A. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr. Med. Chem. 2013, 20, 3855–3871. [Google Scholar] [CrossRef] [PubMed]
  40. Zamarbide, M.; Etayo-Labiano, I.; Ricobaraza, A.; Martínez-Pinilla, E.; Aymerich, M.S.; Lanciego, L.J.; Pérez-Mediavilla, A.; Franco, R. GPR40 activation leads to CREB and ERK phosphorylation in primary cultures of neurons from the mouse CNS and in human neuroblastoma cells. Hippocampus 2014, 24, 733–739. [Google Scholar] [CrossRef] [PubMed]
  41. Srivastava, A.; Yano, J.; Hirozane, Y.; Kefala, G.; Gruswitz, F.; Snell, G.; Lane, W.; Ivetac, A.; Aertgeerts, K.; Nguyen, J.; et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 2014, 513, 124–127. [Google Scholar] [CrossRef] [PubMed]
  42. Hirasawa, A.; Tsumaya, K.; Awaji, T.; Katsuma, S.; Adachi, T.; Yamada, M.; Sugimoto, Y.; Miyazaki, S.; Tsujimoto, G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 2005, 11, 90–94. [Google Scholar] [CrossRef] [PubMed]
  43. Hara, T.; Hirasawa, A.; Sun, Q.; Sadakane, K.; Itsubo, C.; Iga, T.; Adachi, T.; Koshimizu, T.A.; Hashimoto, T.; Asakawa, Y.; et al. Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn Schmiedebergs Arch. Pharmacol. 2009, 380, 247–255. [Google Scholar] [CrossRef] [PubMed]
  44. Katsuma, S.; Hatae, N.; Yano, T.; Ruike, Y.; Kimura, M.; Hirasawa, A.; Tsujimoto, G. Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1. J. Biol. Chem. 2005, 280, 19507–19515. [Google Scholar] [PubMed]
  45. Oh, D.Y.; Talukdar, S.; Bae, E.J.; Imamura, T.; Morinaga, H.; Fan, W.; Li, P.; Lu, W.J.; Watkins, S.M.; Olefsky, J.M. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010, 142, 687–698. [Google Scholar] [CrossRef] [PubMed]
  46. Sidhu, S.S.; Thompson, D.G.; Warhurst, G.; Case, R.M.; Benson, R.S. Fatty acid-induced cholecystokinin secretion and changes in intracellular Ca2+ in two enteroendocrine cell lines, STC-1 and GLUTag. J. Physiol. 2000, 528, 165–176. [Google Scholar] [CrossRef] [PubMed]
  47. Tanaka, T.; Katsuma, S.; Adachi, T.; Koshimizu, T.A.; Hirasawa, A.; Tsujimoto, G. Free fatty acids induce cholecystokinin secretion through GPR120. Naunyn Schmiedebergs Arch. Pharmacol. 2008, 377, 523–527. [Google Scholar] [CrossRef] [PubMed]
  48. Gotoh, C.; Hong, Y.H.; Iga, T.; Hishikawa, D.; Suzuki, Y.; Song, S.H.; Choi, K.C.; Adachi, T.; Hirasawa, A.; Tsujimoto, G.; et al. The regulation of adipogenesis through GPR120. Biochem. Biophys. Res. Commun. 2007, 354, 591–597. [Google Scholar] [CrossRef] [PubMed]
  49. Ichimura, A.; Hirasawa, A.; Poulain-Godefroy, O.; Bonnefond, A.; Hara, T.; Yengo, L.; Kimura, I.; Leloire, A.; Liu, N.; Iida, K.; et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 2012, 483, 350–354. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Oh, D.Y.; Walenta, E.; Akiyama, T.E.; Lagakos, W.S.; Lackey, D.; Pessentheiner, A.R.; Sasik, R.; Hah, N.; Chi, T.J.; Cox, J.M.; et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 2014, 20, 942–947. [Google Scholar]
  51. Tazoe, H.; Otomo, Y.; Karaki, S.; Kato, I.; Fukami, Y.; Terasaki, M.; Kuwahara, A. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res. 2009, 30, 149–156. [Google Scholar] [CrossRef] [PubMed]
  52. Samuel, B.S.; Shaito, A.; Motoike, T.; Rey, F.E.; Backhed, F.; Manchester, J.K.; Hammer, R.E.; Williams, S.C.; Crowley, J.; Yanagisawa, M.; et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA 2008, 105, 16767–16772. [Google Scholar] [CrossRef] [PubMed]
  53. Tolhurst, G.; Heffron, H.; Lam, Y.S.; Parker, H.E.; Habib, A.M.; Diakogiannaki, E.; Cameron, J.; Grosse, J.; Reimann, F.; Gribble, F.M. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012, 61, 364–371. [Google Scholar] [CrossRef] [PubMed]
  54. Kimura, I.; Inoue, D.; Maeda, T.; Hara, T.; Ichimura, A.; Miyauchi, S.; Kobayashi, M.; Hirasawa, A.; Tsujimoto, G. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. USA 2011, 108, 8030–8035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. De Vadder, F.; Kovatcheva-Datchary, P.; Goncalves, D.; Vinera, J.; Zitoun, C.; Duchampt, A.; Bäckhed, F.; Mithieux, G. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014, 156, 84–96. [Google Scholar]
  56. Tang, C.; Ahmed, K.; Gille, A.; Lu, S.; Gröne, H.J.; Tunaru, S.; Offermanns, S. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 2015, 21, 173–177. [Google Scholar] [CrossRef] [PubMed]
  57. Karaki, S.; Mitsui, R.; Hayashi, H.; Kato, I.; Sugiya, H.; Iwanaga, T.; Furness, J.B.; Kuwahara, A. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 2006, 324, 353–360. [Google Scholar] [CrossRef] [PubMed]
  58. Darzi, J.; Frost, G.S.; Robertson, M.D. Do SCFA have a role in appetite regulation? Proc. Nutr. Soc. 2011, 70, 119–128. [Google Scholar] [CrossRef] [PubMed]
  59. Hudson, B.D.; Due-Hansen, M.E.; Christiansen, E.; Hansen, A.M.; Mackenzie, A.E.; Murdoch, H.; Pandey, S.K.; Ward, R.J.; Marquez, R.; Tikhonova, I.G.; et al. Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J. Biol. Chem. 2013, 288, 17296–17312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Hong, Y.H.; Nishimura, Y.; Hishikawa, D.; Tsuzuki, H.; Miyahara, H.; Gotoh, C.; Choi, K.C.; Feng, D.D.; Chen, C.; Lee, H.G.; et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 2005, 146, 5092–5099. [Google Scholar] [CrossRef] [PubMed]
  61. Ge, H.; Li, X.; Weiszmann, J.; Wang, P.; Baribault, H.; Chen, J.L.; Tian, H.; Li, Y. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 2008, 149, 4519–4526. [Google Scholar] [CrossRef] [PubMed]
  62. Kimura, I.; Ozawa, K.; Inoue, D.; Imamura, T.; Kimura, K.; Maeda, T.; Terasawa, K.; Kashihara, D.; Hirano, K.; Tani, T.; et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 2013, 4, 1829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Kimura, I.; Inoue, D.; Hirano, K.; Tsujimoto, G. The SCFA Receptor GPR43 and Energy Metabolism. Front. Endocrinol. Lausanne 2014, 5, 85. [Google Scholar] [CrossRef] [PubMed]
  64. Kuwahara, A. Contributions of colonic short-chain fatty acid receptors in energy homeostasis. Front. Endocrinol. Lausanne 2014, 5, 144. [Google Scholar] [CrossRef] [PubMed]
  65. Maslowski, K.M.; Vieira, A.T.; Ng, A.; Kranich, J.; Sierro, F.; Yu, D.; Schilter, H.C.; Rolph, M.S.; Mackay, F.; Artis, D.; et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009, 461, 1282–1286. [Google Scholar] [CrossRef] [PubMed]
  66. Sina, C.; Gavrilova, O.; Förster, M.; Till, A.; Derer, S.; Hildebrand, F.; Raabe, B.; Chalaris, A.; Scheller, J.; Rehmann, A.; et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 2009, 183, 7514–7522. [Google Scholar] [CrossRef] [PubMed]
  67. Cox, M.A.; Jackson, J.; Stanton, M.; Rojas-Triana, A.; Bober, L.; Laverty, M.; Yang, X.; Zhu, F.; Liu, J.; Wang, S.; et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E2 and cytokines. World J. Gastroenterol. 2009, 15, 5549–5557. [Google Scholar] [CrossRef] [PubMed]
  68. Smith, P.M.; Howitt, M.R.; Panikov, N.; Michaud, M.; Gallini, C.A.; Bohlooly-Y, M.; Glickman, J.N.; Garrett, W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013, 341, 569–573. [Google Scholar] [CrossRef] [PubMed]
  69. Bindels, L.B.; Dewulf, E.M.; Delzenne, N.M. GPR43/FFA2: Physiopathological relevance and therapeutic prospects. Trends Pharmacol. Sci. 2013, 34, 226–232. [Google Scholar] [CrossRef] [PubMed]
  70. Overton, H.A.; Babbs, A.J.; Doel, S.M.; Fyfe, M.C.; Gardner, L.S.; Griffin, G.; Jackson, H.C.; Procter, M.J.; Rasamison, C.M.; Tang-Christensen, M.; et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006, 3, 167–175. [Google Scholar] [CrossRef] [PubMed]
  71. Hansen, K.B.; Vilsbøll, T.; Bagger, J.I.; Holst, J.J.; Knop, F.K. Increased postprandial GIP and glucagon responses, but unaltered GLP-1 response after intervention with steroid hormone, relative physical inactivity, and high-calorie diet in healthy subjects. J. Clin. Endocrinol. Metab. 2011, 96, 447–453. [Google Scholar] [CrossRef] [PubMed]
  72. Odori, S.; Hosoda, K.; Tomita, T.; Fujikura, J.; Kusakabe, T.; Kawaguchi, Y.; Doi, R.; Takaori, K.; Ebihara, K.; Sakai, Y.; et al. GPR119 expression in normal human tissues and islet cell tumors: Evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. Metabolism 2013, 62, 70–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Soga, T.; Ohishi, T.; Matsui, T.; Saito, T.; Matsumoto, M.; Takasaki, J.; Matsumoto, S.; Kamohara, M.; Hiyama, H.; Yoshida, S.; et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem. Biophys. Res. Commun. 2005, 326, 744–751. [Google Scholar] [CrossRef] [PubMed]
  74. Chu, Z.L.; Carroll, C.; Chen, R.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Xing, C.; Sebring, K.; Zhou, J.; et al. N-Oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol. Endocrinol. 2010, 24, 161–170. [Google Scholar] [CrossRef] [PubMed]
  75. Chu, Z.L.; Jones, R.M.; He, H.; Carroll, C.; Gutierrez, V.; Lucman, A.; Moloney, M.; Gao, H.; Mondala, H.; Bagnol, D.; et al. A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 2007, 148, 2601–2609. [Google Scholar] [CrossRef] [PubMed]
  76. Lan, H.; Lin, H.V.; Wang, C.F.; Wright, M.J.; Xu, S.; Kang, L.; Juhl, K.; Hedrick, J.A.; Kowalski, T.J. Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. Br. J. Pharmacol. 2012, 165, 2799–2807. [Google Scholar] [CrossRef] [PubMed]
  77. Wang, J.; Wu, X.; Simonavicius, N.; Tian, H.; Ling, L. Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J. Biol. Chem. 2006, 281, 34457–34464. [Google Scholar] [CrossRef] [PubMed]
  78. Lattin, J.E.; Schroder, K.; Su, A.I.; Walker, J.R.; Zhang, J.; Wiltshire, T.; Saijo, K.; Glass, C.K.; Hume, D.A.; Kellie, S.; et al. Expression analysis of G protein-coupled receptors in mouse macrophages. Immunome Res. 2008, 4, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Venkataraman, C.; Kuo, F. The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol. Lett. 2005, 101, 144–153. [Google Scholar] [CrossRef] [PubMed]
  80. Nagasaki, H.; Kondo, T.; Fuchigami, M.; Hashimoto, H.; Sugimura, Y.; Ozaki, N.; Arima, H.; Ota, A.; Oiso, Y.; Hamada, Y. Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes. FEBS Lett. 2012, 586, 368–372. [Google Scholar] [CrossRef] [PubMed]
Ijms 17 00450 g001 1024
Figure 1. Effects of fatty acids (including SC- and LCFAs) derived from the diet by gut microbiota on the regulation of host metabolic and immune functions.
Figure 1. Effects of fatty acids (including SC- and LCFAs) derived from the diet by gut microbiota on the regulation of host metabolic and immune functions.
Ijms 17 00450 g001
Table
Table 1. Affinity of free fatty acids for GPR41, GPR43, GPR40 and GPR120 [29].
Table 1. Affinity of free fatty acids for GPR41, GPR43, GPR40 and GPR120 [29].
LigandEC50 of Ligand Affinity (μM)
GPR41/FFAR3GPR43/FFAR2GPR40/FFAR1GPR120/FFAR4
Saturated fatty acids
acetic acid (C2:0)>1000 (b–d)35–431 (b–d)
propionic acid (C3:0)6–127 (b–d)14–290 (b–d)
butyric acid (C4:0)42–158 (b–d)28–371 (b–d)
valeric acid (C5:0)42–142 (b–d)>1000 (b–d)
caproic acid (C6:0)102–134 (a,c,d) 46 (a,c,d)
caprylate (C8:0) 38 (a)
capric acid (C10:0) 14–43 (a,d)
lauric acid (C12:0) 6–12 (a,d)
myristic acid (C14:0) 8–14 (a,d)30 (a,d)
palmitic acid (C16:0) 5–7 (a,d)52 (a,d)
stearic acid (C18:0) 17 (a)18 (a)
Monounsaturated fatty acids
palmitoleic acid (C16:1, n-7) 14 (a)0.7–3 (a)
oleic acid (C18:1, n-9) 2–40 (a,d)31 (a,d)
ω-3 fatty acids
α-linolenic acid (C18:3, n-3) 2–13 (a,d)0.5 (a,d)
cis-11,14,17-eicosatrienoic acid (C20:3, n-3) 11 (a)1 (a)
cis-5,8,11,14,17-eicosapentaenoic acid (C20:5, n-3) 2–7 (a,d)2–3 (a,d)
docosahexaenoic acid (22:6, n-3) 1–4 (a,d)4 (a,d)
ω -6 fatty acids
linoleic acid (C18:2, n-6) 2–10 (a,d)1 (a,d)
γ-linolenic acid (C18:3, n-6) 5–9 (a,d)1 (a,d)
dihomo-γ-linolenic acid (C20:4, n-6) 7 (a)14 (a)
arachidonic acid (C20:4, n-6) 2–12 (a,d)
docosatetraenoic acid (C22:4, n-6) 13 (a)16 (a)
Measured as induction of [Ca2+]i (a) and GTPγs (b) in each FFARs-transfected HEK293 cells, or cAMP (c) and [Ca2+]i (d) in each FFARs-transfected CHO cells.
Table
Table 2. Affinity of representative compounds including fatty acids for GPR119 [74].
Table 2. Affinity of representative compounds including fatty acids for GPR119 [74].
LigandEC50 (μM)
all trans-retinoic acidno response
C18:1 LPCno response
oleoylethanolamide (OEA)4.4
Z-capsaicinno response
olvanil7.8
N-oleoyldopamine (OLDA)3.2
(R)-N-oleoyltyrosinol0.5
(S)-N-oleoyltyrosinol0.7
N-oleoyltryosineno response
N-arachidonyldopamine (NADA)no response
Measured as induction of cAMP in GPR119-transfected HEK293 cells.
Table
Table 3. Affinity of various fatty acids for GPR84 [77].
Table 3. Affinity of various fatty acids for GPR84 [77].
LigandEC50 (μM)
formic acid (C1:0)no response
acetic acid (C2:0)no response
propionic acid (C3:0)no response
butyric acid (C4:0)no response
caproic acid (C6:0)no response
heptanoic acid (C7:0)no response
caprylic acid (C8:0)no response
nonanoic acid (C9:0)52.3 ± 5.6
capric acid (C10:0)4.5 ± 0.3
undecanoic acid (C11:0)7.7 ± 0.1
lauric acid (C12:0)8.8 ± 0.2
tridecanoic acid (C13:0)24.8 ± 1.1
myristic acid (C14:0)93.2 ± 11.0
pentadeconoic acid (C15:0)no response
palmitic acid (C16:0)no response
heptadecanoic acid (C17:0)no response
stearic acid (C18:0)no response
arachidic acid (C20:0)no response
heneicosanoic acid (C21:0)no response
behenic acid (C22:0)no response
palmitoleic acid (C16:1)no response
oleic acid (C18:1)no response
elaidic acid (C18:1)no response
linoleic acid (C18:2)no response
α-linolenic acid (C18:3)no response
γ-linolenic acid (C18:3)no response
cis-11,14,17-eicosatrienoic acid (C20:3)no response
arachidonic acid (C20:4)no response
cis-5,8,11,14,17-eicosapentaenoic acid (C20:5)no response
docosahexaenoic acid (C22:6)no response
Measured as induction of cAMP in GPR84-transfected CHO cells.

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Miyamoto, J.; Hasegawa, S.; Kasubuchi, M.; Ichimura, A.; Nakajima, A.; Kimura, I. Nutritional Signaling via Free Fatty Acid Receptors. Int. J. Mol. Sci. 2016, 17, 450. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040450

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Miyamoto J, Hasegawa S, Kasubuchi M, Ichimura A, Nakajima A, Kimura I. Nutritional Signaling via Free Fatty Acid Receptors. International Journal of Molecular Sciences. 2016; 17(4):450. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040450

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Miyamoto, Junki, Sae Hasegawa, Mayu Kasubuchi, Atsuhiko Ichimura, Akira Nakajima, and Ikuo Kimura. 2016. "Nutritional Signaling via Free Fatty Acid Receptors" International Journal of Molecular Sciences 17, no. 4: 450. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040450

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