Abstract
Chronic low-grade inflammation in macrophages and adipose tissues can promote the development of obesity and type 2 diabetes. Free fatty acids (FFAs) have important roles in various tissues, acting as both essential energy sources and signaling molecules. FFA receptors (FFARs) can modulate inflammation in various types of cells and tissues; however the underlying mechanisms mediating these effects are unclear. FFARs are activated by specific FFAs; for example, GPR40 and GPR120 are activated by medium and long chain FFAs, GPR41 and GPR43 are activated by short chain FFAs, and GPR84 is activated by medium-chain FFAs. To date, a number of studies associated with the physiological functions of G protein-coupled receptors (GPCRs) have reported that these GPCRs are expressed in various tissues and involved in inflammatory and metabolic responses. Thus, the development of selective agonists or antagonists for various GPCRs may facilitate the establishment of novel therapies for the treatment of various diseases. In this review, we summarize current literature describing the potential of GPCRs as therapeutic targets for inflammatory and metabolic disorders.
Author Contributions: All authors contributed equally to the preparation of the manuscript.
Conflict of Interest: The authors declare no conflict of interest.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bouchard C et al (2007) G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions. Glia 55(8):790–800
Briscoe CP et al (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278(13):11303–11311
Brown AJ et al (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278(13):11312–11319
da Oh Y et al (2014) A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med 20(8):942–947
den Besten G et al (2013) The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54(9):2325–2340
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107
Donohoe DR et al (2011) The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 13(5):517–526
Facchini FS et al (2001) Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 86(8):3574–3578
Fujita T et al (2011) A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation. J Invest Dermatol 131(8):1660–1667
Fukuda S et al (2013) Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469(7331):543–547
Galisteo M, Duarte J, Zarzuelo A (2008) Effects of dietary fibers on disturbances clustered in the metabolic syndrome. J Nutr Biochem 19(2):71–84
Gao Z et al (2009) Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58(7):1509–1517
Gether U (2000) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 21(1):90–113
Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445
Hara T, Ichimura A, Hirasawa A (2014) Therapeutic role and ligands of medium- to long-chain fatty acid receptors. Front Endocrinol (Lausanne) 5:83
Harig JM et al (1989) Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 320(1):23–28
Hudson BD et al (2013) Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288(24):17296–17312
Ichimura A et al (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483(7389):350–354
Itoh Y et al (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422(6928):173–176
Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444(7121):840–846
Kim MH et al (2013) Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145(2):396–406
Kimura I et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 108(19):8030–8035
Kimura I et al (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4:1829
Kotarsky K et al (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301(2):406–410
Lattin JE et al (2008) Expression analysis of G protein-coupled receptors in mouse macrophages. Immunome Res 4:5
Le Poul E et al (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278(28):25481–25489
Maslowski KM et al (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461(7268):1282–1286
Masui R et al (2013) G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm Bowel Dis 19(13):2848–2856
McNelis JC et al (2015) GPR43 potentiates β-cell function in obesity. Diabetes 64(9):3203–3217
Miyamoto J et al (2015) 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 290(5):2902–2918
Morari J et al (2010) The role of proliferator-activated receptor gamma coactivator-1alpha in the fatty-acid-dependent transcriptional control of interleukin-10 in hepatic cells of rodents. Metabolism 59(2):215–223
Nagasaki H et al (2012) Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes. FEBS Lett 586(4):368–372
Nilsson NE (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303(4):1047–1052
Oh DY et al (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142(5):687–698
Oliveira V et al (2015) Diets containing α-linolenic (ω3) or oleic (ω9) fatty acids rescues obese mice from insulin resistance. Endocrinology 156(11):4033–4046
Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18(3):363–374
Park J et al (2015) Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8(1):80–93
Parker HE et al (2009) Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52(2):289–298
Pivovarova O et al (2015) Regulation of nutrition-associated receptors in blood monocytes of normal weight and obese humans. Peptides 65:12–19
Schulte G, Fredholm BB (2003) Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 15(9):813–827
Seidell JC (2000) Obesity, insulin resistance and diabetes—a worldwide epidemic. Br J Nutr 83(Suppl 1):S5–S8
Sina C et al (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183(11):7514–7522
Takeuchi H et al (2006) Lower weight gain and higher expression and blood levels of adiponectin in rats fed medium-chain TAG compared with long-chain TAG. Lipids 41(2):207–212
Tazoe H et al (2009) Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res 30(3):149–156
Tolhurst G et al (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61(2):364–371
Tomita T et al (2014) The G-protein-coupled long-chain fatty acid receptor GPR40 and glucose metabolism. Front Endocrinol (Lausanne) 5:152
Trompette A et al (2014) Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20(2):159–166
Turner N et al (2009) Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species dependent: potent tissue-specific effects of medium-chain fatty acids. Diabetes 58(11):2547–2554
Venkataraman C, Kuo F (2005) The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol Lett 101(2):144–153
Wang J et al (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem 281(45):34457–34464
Wang X et al (2015) Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway. Sci Rep 5:12676
Wein S et al (2009) Medium-chain fatty acids ameliorate insulin resistance caused by high-fat diets in rats. Diabetes Metab Res Rev 25(2):185–194
Xiong Y et al (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci U S A 101(4):1045–1050
Yousefi S et al (2001) Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes. J Leukoc Biol 69(6):1045–1052
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Miyamoto, J., Kasubuchi, M., Nakajima, A., Kimura, I. (2016). Anti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors. In: Milligan, G., Kimura, I. (eds) Free Fatty Acid Receptors. Handbook of Experimental Pharmacology, vol 236. Springer, Cham. https://doi.org/10.1007/164_2016_47
Download citation
DOI: https://doi.org/10.1007/164_2016_47
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-50692-0
Online ISBN: 978-3-319-50693-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)