free fatty acid receptor 3

The human FFAR3 gene is located next to the FFAR2 gene at locus 13.12 on the long (i.e., "q") arm of chromosome 19 (location abbreviated as 19q13.12).

Studies have reported that humans express FFAR3 in their: (a) enteroendocrine L cells and K cells of the intestines; (b) endothelium of blood vessels in the frontal cortex of the brain,{{cite journal | vauthors = Hoyles L, Snelling T, Umlai UK, Nicholson JK, Carding SR, Glen RC, McArthur S | title = Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier | journal = Microbiome | volume = 6 | issue = 1 | article-number = 55 | date = March 2018 | pmid = 29562936 | pmc = 5863458 | doi = 10.1186/s40168-018-0439-y | doi-access = free }} pancreatic β-cells,{{cite journal | vauthors = Teyani R, Moniri NH | title = Gut feelings in the islets: The role of the gut microbiome and the FFA2 and FFA3 receptors for short chain fatty acids on β-cell function and metabolic regulation | journal = British Journal of Pharmacology | volume = 180 | issue = 24 | pages = 3113–3129 | date = December 2023 | pmid = 37620991 | doi = 10.1111/bph.16225 | s2cid = 261121846 }} and adipose. i.e., fat, tissue (but not in mouse adipose tissue);{{cite journal | vauthors = Al Mahri S, Malik SS, Al Ibrahim M, Haji E, Dairi G, Mohammad S | title = Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook | journal = Cells | volume = 11 | issue = 4 | page = 750 | date = February 2022 | pmid = 35203397 | pmc = 8870169 | doi = 10.3390/cells11040750 | doi-access = free }} (c) the vascular endothelium of the myometrium, the epithelium of the amnion, chorion and placenta, and certain immune cells in these tissues of pregnant women;{{cite journal | vauthors = Voltolini C, Battersby S, Etherington SL, Petraglia F, Norman JE, Jabbour HN | title = A novel antiinflammatory role for the short-chain fatty acids in human labor | journal = Endocrinology | volume = 153 | issue = 1 | pages = 395–403 | date = January 2012 | pmid = 22186417 | doi = 10.1210/en.2011-1457 | hdl-access = free | s2cid = 34431654 | doi-access = free | hdl = 20.500.11820/7035e8fd-062a-491a-9943-f20ad03844dd }} (d) the hippocampus of the brain;{{cite journal | vauthors = Zamarbide M, Martinez-Pinilla E, Gil-Bea F, Yanagisawa M, Franco R, Perez-Mediavilla A | title = Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APP_swe Alzheimer's Disease Mouse Model | journal = International Journal of Molecular Sciences | volume = 23 | issue = 7 | page = 3533 | date = March 2022 | pmid = 35408893 | pmc = 8999053 | doi = 10.3390/ijms23073533 | doi-access = free }} (e) sympathetic ganglia, i.e., autonomic ganglia of the sympathetic nervous system;{{cite journal | vauthors = Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G | title = Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 19 | pages = 8030–8035 | date = May 2011 | pmid = 21518883 | pmc = 3093469 | doi = 10.1073/pnas.1016088108 | doi-access = free | bibcode = 2011PNAS..108.8030K }} (f) certain types of immune cells, i.e., blood monocytes (but not mouse monocytes), basophils,{{cite journal | vauthors = Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S, Monsma F, Vassileva G, Maguire M, Gustafson E, Bayne M, Chou CC, Lundell D, Jenh CH | title = Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines | journal = World Journal of Gastroenterology | volume = 15 | issue = 44 | pages = 5549–5557 | date = November 2009 | pmid = 19938193 | pmc = 2785057 | doi = 10.3748/wjg.15.5549 | doi-access = free }} dendritic cells derived from human monocytes isolated from whole blood, and the tissues containing these blood cells, i.e., the bone marrow, spleen, lymph nodes, and thymus;{{cite journal | vauthors = Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M | title = Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 25481–25489 | date = July 2003 | pmid = 12711604 | doi = 10.1074/jbc.M301403200 | doi-access = free }} and (g) alveolar macrophages, and macrophages in various other tissues; and (h) certain immortalised cell lines, i.e., MCF-7 breast cancer,{{cite journal | vauthors = Yonezawa T, Kobayashi Y, Obara Y | title = Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line | journal = Cellular Signalling | volume = 19 | issue = 1 | pages = 185–193 | date = January 2007 | pmid = 16887331 | doi = 10.1016/j.cellsig.2006.06.004 }} HCT116 colorectal cancer,{{cite journal | vauthors = Al Mahri S, Al Ghamdi A, Akiel M, Al Aujan M, Mohammad S, Aziz MA | title = Free fatty acids receptors 2 and 3 control cell proliferation by regulating cellular glucose uptake | journal = World Journal of Gastrointestinal Oncology | volume = 12 | issue = 5 | pages = 514–525 | date = May 2020 | pmid = 32461783 | pmc = 7235185 | doi = 10.4251/wjgo.v12.i5.514 | doi-access = free }} HEK293 embryonic kidney,{{cite journal | vauthors = Miyasato S, Iwata K, Mura R, Nakamura S, Yanagida K, Shindou H, Nagata Y, Kawahara M, Yamaguchi S, Aoki J, Inoue A, Nagamune T, Shimizu T, Nakamura M | title = Constitutively active GPR43 is crucial for proper leukocyte differentiation | journal = FASEB Journal | volume = 37 | issue = 1 | pages = e22676 | date = January 2023 | pmid = 36468834 | doi = 10.1096/fj.202201591R | s2cid = 254244683 | doi-access = free }} U937 leukemic promonocyte, THP-1 leukemic monocyte, EoL-1 leukemic eosinophil, Jurcat leukemic T lymphocyte, MOLT-4 T lymphoblast leukemic, and HL60 acute myeloid leukemia cells (but only when the HL60 cells are pre-treated with phorbol 12-myristate 13-acetate to promote their cellular differentiation). As noted, the expression of FFAR3 in the cells and tissues of animals are not always the same as those in humans.

Free fatty acid receptor 3 is a member of the G protein-coupled receptor (GPCR) superfamily, characterized by its seven transmembrane alpha-helices. FFAR3 shares significant sequence similarity with FFAR2 but exhibits distinct structural features that influence its ligand specificity and signaling. The receptor’s orthosteric binding pocket is formed by transmembrane helices 3, 4, and 5, with key conserved residues such as

Arg-185 (5.39), Arg-255 (7.35), His-140 (4.56), and His-242 (6.55) contributing to the binding and recognition of short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate. Notably, FFAR3’s binding cavity is more hydrophilic compared to its close relative FFAR2, which affects its ligand interactions. The second extracellular loop is important in modulating ligand selectivity and receptor activation. Additionally, the presence of a His-45 (2.40) is predicted to coordinate allosteric modulators.{{cite journal | vauthors = Milligan G, Stoddart LA, Smith NJ | title = Agonism and allosterism: the pharmacology of the free fatty acid receptors FFA2 and FFA3 | journal = British Journal of Pharmacology | volume = 158 | issue = 1 | pages = 146–53 | date = September 2009 | pmid = 19719777 | pmc = 2795255 | doi = 10.1111/j.1476-5381.2009.00421.x }}{{cite journal | vauthors = Tikhonova IG, Poerio E | title = Free fatty acid receptors: structural models and elucidation of ligand binding interactions | journal = BMC Structural Biology | volume = 15 | issue = | article-number = 16 | date = September 2015 | pmid = 26346819 | pmc = 4561419 | doi = 10.1186/s12900-015-0044-2 | doi-access = free }}

The human FFAR3 and FFAR2 proteins consist of 346 and 330 amino acids, respectively,{{cite journal | vauthors = Mishra SP, Karunakar P, Taraphder S, Yadav H | title = Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View | journal = Biomedicines | volume = 8 | issue = 6 | page = 154 | date = June 2020 | pmid = 32521775 | pmc = 7344995 | doi = 10.3390/biomedicines8060154 | doi-access = free }} and share about a 40% amino acid sequence homology.{{cite journal | vauthors = Secor JD, Fligor SC, Tsikis ST, Yu LJ, Puder M | title = Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease | journal = Frontiers in Physiology | volume = 12 | issue = | pages = 656441 | date = 2021 | pmid = 33897464 | pmc = 8058363 | doi = 10.3389/fphys.2021.656441 | doi-access = free }} The two FFARs have been found to form a heteromer complex (i.e., FFAR3 and FFAR2 bind to each other and are activated together by a SC-FA). When stimulated by a SC-FA, the cells expressing both FFAR3 and FFAR2 may form this heterodimer and thereby activate cell signaling pathways and mount responses that differ from those of cells expressing only one of these FFARs.{{cite journal | vauthors = Ang Z, Xiong D, Wu M, Ding JL | title = FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing | journal = FASEB Journal | volume = 32 | issue = 1 | pages = 289–303 | date = January 2018 | pmid = 28883043 | pmc = 5731126 | doi = 10.1096/fj.201700252RR | doi-access = free }} The formation of GPR43-GPR41 heterodimers has not been evaluated in most studies and may explain otherwise conflicting results on the roles of FFAR3 and FFAR2 in cell function.{{cite journal | vauthors = Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N | title = SCFA: mechanisms and functional importance in the gut | journal = The Proceedings of the Nutrition Society | volume = 80 | issue = 1 | pages = 37–49 | date = February 2021 | pmid = 32238208 | doi = 10.1017/S0029665120006916 | s2cid = 214772999 | doi-access = free }}{{cite journal | vauthors = Ang Z, Er JZ, Tan NS, Lu J, Liou YC, Grosse J, Ding JL | title = Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists | journal = Scientific Reports | volume = 6 | article-number = 34145 | date = September 2016 | pmid = 27667443 | pmc = 5036191 | doi = 10.1038/srep34145 | bibcode = 2016NatSR...634145A }} Furthermore, SC-FAs can alter the function of cells independently of FFAR3 and FFAR2 by altering the activity of cellular histone deacetylases which regulate the transcription of various genes or by altering metabolic pathways which alter cell functions.{{cite journal | vauthors = Carretta MD, Quiroga J, López R, Hidalgo MA, Burgos RA | title = Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer | journal = Frontiers in Physiology | volume = 12 | issue = | pages = 662739 | date = 2021 | pmid = 33897470 | pmc = 8060628 | doi = 10.3389/fphys.2021.662739 | doi-access = free }}{{cite journal | vauthors = Tan JK, Macia L, Mackay CR | title = Dietary fiber and SCFAs in the regulation of mucosal immunity | journal = The Journal of Allergy and Clinical Immunology | volume = 151 | issue = 2 | pages = 361–370 | date = February 2023 | pmid = 36543697 | doi = 10.1016/j.jaci.2022.11.007 | s2cid = 254918066 }} Given these alternate ways for SC-FAs to activate cells as well as the ability of SC-FAs to activate FFAR2 or, in the case of butyric acid, hydroxycarboxylic acid receptor 2, the studies reported here focus on those showing that the examined action(s) of an SC-FA is absent or reduced in cells, tissues, or animals that have no or reduced FFAR3 activity due respectively to knockout (i.e., removal or inactivation) or knockdown (i.e., reduction) of the FFAR3 protein gene, i.e., the Ffar3 gene in animals or FFAR3 gene in humans.

L cells are enteroendocrine cells, i.e., specialized cells that secrete hormones directly into the circulation. L cells reside in the epithelium of the gastrointestinal tract, particularly the terminal ileum and colon. They are stimulated to secrete PYY (also termed peptide YY) and GLP-1 (also termed glucagon-like peptide-1) by the SC-FAs that accumulate inside the intestines after feeding. L cells express FFAR3 and/or FFAR2. Ffar3 and Ffar2 gene knock out mice show reduced secretions of GLP-1 and PYY.{{cite journal | vauthors = de Vos WM, Tilg H, Van Hul M, Cani PD | title = Gut microbiome and health: mechanistic insights | journal = Gut | volume = 71 | issue = 5 | pages = 1020–1032 | date = May 2022 | pmid = 35105664 | pmc = 8995832 | doi = 10.1136/gutjnl-2021-326789 }}

Leptin is a peptide hormone released by adipose tissue that triggers satiety and thereby tends to reduce or stop further food intake and the development of obesity. It also plays a role in female reproductive function, lipolysis (e.g., the breakdown of triglycerides into their component free fatty acids and glycerol), the growth of fetuses, inflammation, and angiogenesis (i.e., the formation of new blood vessels from pre-existing blood vessels). While studies have suggested that the SC-FA-induced activation of FFAR3 leads to the secretion of leptin from the white adipose tissue of intact animals and the fat tissue isolated from human tissues, other studies have suggested that FFAR2 rather than FFAR3 is responsible for the SC-FA-induced release of leptin from fat tissue. A systematic review of the published studies on this issue concluded that SC-FA-induced activation of FFAR3 is likely responsible for the SC-FA-induced release of leptin from cultured fat tissue taken from animals. However, the data were insufficient to support a role for FFAR3 in the release of leptin from cultured human fat tissues or the fat tissue of intact animals. The role of FFAR3 stimulation of leptin release in appetite suppression and obesity needs further study.{{cite journal | vauthors = Gabriel FC, Fantuzzi G | title = The association of short-chain fatty acids and leptin metabolism: a systematic review | journal = Nutrition Research | volume = 72 | issue = | pages = 18–35 | date = December 2019 | pmid = 31669116 | doi = 10.1016/j.nutres.2019.08.006 | s2cid = 155928278 | url = https://figshare.com/articles/thesis/The_Association_of_Short-Chain_Fatty_Acids_and_Leptin_Metabolism_A_Systematic_Review/10901015 }}

In a high-fat diet-induced obesity model of fatty liver disease (i.e., excessive buildup of fat in the liver), mice fed a diet that increased intestinal levels of SC-FAs showed reductions in their livers' synthesis of lipids, triglyceride levels, and weights. These reductions did not occur in Ffar3 gene knockout mice but did occur in Ffar2 gene knocked-out mice. These results indicate that the SC-FA-induced activation of FFAR3 suppresses the liver's accumulation of fatty acids that underlies the development of fatty liver disease in this mouse model.

Other studies have found that Ffar3 gene knockout mice showed less weight gain than wild-type mice under standard laboratory conditions, but this difference was lost in mice reared under germ-free conditions (i.e., which causes the mice to have lower intestinal and tissue levels of SC-FAs). These findings indicated that the activation of FFAR3 but not FFAR2 by SC-FAs protects against developing fatty liver disease in mice.

Individuals with type 2 diabetes, which accounts for 90% of all diabetes cases, have decreases in the proliferation, maturation, and activity of their pancreatic islet insulin-secreting beta-cells as well as the potency of insulin's actions. These decreases result in reduced insulin secretion, hyperglycemia, and the many other afflictions associated with this disorder.

Studies in the past have reported that the activation of FFAR3 reduced the insulin secreted by (1) human and mouse beta cells in vivo, (2) cultured human and murine beta cell-containing pancreatic islets, and (3) cultured beta cell lines. These studies showed that acetic acid-induced inhibition of insulin secretion by mouse pancreatic islets did not occur in islets that had both of their Ffar3 and Ffar2 genes knocked out but had no effect on insulin secretion in islets that had only one of the two genes knocked out.

An early study showed that the intravenous injection of propionic acid into mice induced a brief (<5 min) hypotensive response as defined by drops in their mean arterial pressures. This response was reduced in mice that had one of their two Ffar3 genes knocked out and absent in mice that had both Ffar3 genes knocked out.{{cite journal | vauthors = Pluznick JL | title = Microbial Short-Chain Fatty Acids and Blood Pressure Regulation | journal = Current Hypertension Reports | volume = 19 | issue = 4 | article-number = 25 | date = April 2017 | pmid = 28315048 | pmc = 5584783 | doi = 10.1007/s11906-017-0722-5 }}

A subsequent study reported that Ffar3 gene knockout mice developed abnormally high pulse pressures (i.e., systolic minus diastolic blood pressures) as well as increased amounts of cardiac collagen and elastin connective tissue and increased cardiac stiffness as evidenced by a reduced rate of heart muscle relaxation measured by pressure-volume loop analysis tau levels.{{cite journal | vauthors = Kaye DM, Shihata WA, Jama HA, Tsyganov K, Ziemann M, Kiriazis H, Horlock D, Vijay A, Giam B, Vinh A, Johnson C, Fiedler A, Donner D, Snelson M, Coughlan MT, Phillips S, Du XJ, El-Osta A, Drummond G, Lambert GW, Spector TD, Valdes AM, Mackay CR, Marques FZ | title = Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease | journal = Circulation | volume = 141 | issue = 17 | pages = 1393–1403 | date = April 2020 | pmid = 32093510 | doi = 10.1161/CIRCULATIONAHA.119.043081 | hdl-access = free | s2cid = 211476145 | doi-access = free | hdl = 10536/DRO/DU:30135388 }}

=== Heart rate and energy expenditure ===

Studies have shown that compared to wild type mice, Ffar3 gene knockout mice have: a) significantly smaller-sized sympathetic nervous system ganglia as judged by measurements of this systems' largest ganglia, the superior cervical ganglion; b) significantly slower heart rates; and c) significantly lower norepinephrine levels in their blood plasma. (Norepinephrine is a neurotransmitter that is released by sympathetic nervous system neurons and among other actions increases heart rate and total body energy expenditure.) Furthermore, the treatment of wild type mice with propionic acid increased their heart rates but did not do so in Ffar3 gene knockout mice. Finally, the offspring of Ffar3-gene knockout mice had slower heart rates (as well as lower body temperatures) than the offspring of wild type mice. These findings indicate that FFAR3 regulates heart rates and energy expenditure in mice. Studies are needed to determine if it does so in humans.

Certain bacteria in the gastrointestinal tract ferment fecal fiber into SC-FAs and excrete them as waste products. The excreted SC-FAs enter the gastrointestinal walls, diffuse into the portal venous system, and ultimately flow into the systemic circulation. During this passage, they can activate the FFAR3 on cells in the intestinal wall as well as throughout the body.{{cite journal | vauthors = Ikeda T, Nishida A, Yamano M, Kimura I | title = Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases | journal = Pharmacology & Therapeutics | volume = 239 | issue = | article-number = 108273 | date = November 2022 | pmid = 36057320 | doi = 10.1016/j.pharmthera.2022.108273 | s2cid = 251992642 | doi-access = free }} This activation may: suppress the appetite for food and thereby reduce overeating and the development of obesity;{{cite journal | vauthors = Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, Gojobori T, Isenovic ER | title = Leptin and Obesity: Role and Clinical Implication | journal = Frontiers in Endocrinology | volume = 12 | issue = | pages = 585887 | date = 2021 | pmid = 34084149 | pmc = 8167040 | doi = 10.3389/fendo.2021.585887 | doi-access = free }}{{cite journal | vauthors = Navalón-Monllor V, Soriano-Romaní L, Silva M, de Las Hazas ML, Hernando-Quintana N, Suárez Diéguez T, Esteve PM, Nieto JA | title = Microbiota dysbiosis caused by dietetic patterns as a promoter of Alzheimer's disease through metabolic syndrome mechanisms | journal = Food & Function | volume = 14 | issue = 16 | pages = 7317–7334 | date = August 2023 | pmid = 37470232 | doi = 10.1039/d3fo01257c | s2cid = 259996464 }} inhibit the liver's accumulation of fatty acids and thereby the development of fatty liver diseases;{{cite journal | vauthors = Shimizu H, Masujima Y, Ushiroda C, Mizushima R, Taira S, Ohue-Kitano R, Kimura I | title = Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3 | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 16574 | date = November 2019 | pmid = 31719611 | pmc = 6851370 | doi = 10.1038/s41598-019-53242-x | bibcode = 2019NatSR...916574S }} decrease blood pressure and thereby the development of hypertension and hypertension-related cardiac diseases;{{cite journal | vauthors = Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F, Wang T, Firestein SJ, Yanagisawa M, Gordon JI, Eichmann A, Peti-Peterdi J, Caplan MJ | title = Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 11 | pages = 4410–4415 | date = March 2013 | pmid = 23401498 | pmc = 3600440 | doi = 10.1073/pnas.1215927110 | doi-access = free | bibcode = 2013PNAS..110.4410P }} modulate insulin secretion and thereby the development and/or symptoms of type 2 diabetes;{{cite journal | vauthors = Ghislain J, Poitout V | title = Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges | journal = Nature Reviews. Endocrinology | volume = 17 | issue = 3 | pages = 162–175 | date = March 2021 | pmid = 33495605 | doi = 10.1038/s41574-020-00459-w | s2cid = 231695737 }} reduce heart rate and blood plasma norepinephrine levels and thereby lower total body energy expenditures; and suppress or delay the development of allergic asthma.{{cite journal | vauthors = Yuan G, Wen S, Zhong X, Yang X, Xie L, Wu X, Li X | title = Inulin alleviates offspring asthma by altering maternal intestinal microbiome composition to increase short-chain fatty acids | journal = PLOS ONE | volume = 18 | issue = 4 | pages = e0283105 | date = 2023 | pmid = 37014871 | pmc = 10072493 | doi = 10.1371/journal.pone.0283105 | doi-access = free | bibcode = 2023PLoSO..1883105Y }}

The specific types of bacteria in the intestines can be modified to increase the number which make SC-FAs by using foods that stimulate the growth of these bacteria (i.e., prebiotics), preparations of SC-FA-producing bacteria (i.e., probiotics), or both methods (see synbiotics).{{cite journal | vauthors = Kim YA, Keogh JB, Clifton PM | title = Probiotics, prebiotics, synbiotics and insulin sensitivity | journal = Nutrition Research Reviews | volume = 31 | issue = 1 | pages = 35–51 | date = June 2018 | pmid = 29037268 | doi = 10.1017/S095442241700018X | doi-access = free }} Individuals with disorders that are associated with low levels of the SC-FA-producing intestinal bacteria may show improvements in their conditions when treated with prebiotics, probiotics, or synbiotics while individuals with disorders associated with high levels of SC-FAs may show improvements in their conditions when treated with methods, e.g., antibiotics, that reduce the intestinal levels of these bacteria. (For information on these treatments see Disorders treated by probiotics and Disorders treated by prebiotics). In addition, drugs are being tested for their ability to act more usefully, potently, and effectively than SC-FAs in stimulating or inhibiting FFAR3 and thereby for treating the disoders that are inhibited or stimulated, respectively, by SC-FAs.{{cite journal | vauthors = Loona DP, Das B, Kaur R, Kumar R, Yadav AK | title = Free Fatty Acid Receptors (FFARs): Emerging Therapeutic Targets for the Management of Diabetes Mellitus | journal = Current Medicinal Chemistry | volume = 30 | issue = 30 | pages = 3404–3440 | date = 2023 | pmid = 36173072 | doi = 10.2174/0929867329666220927113614 | s2cid = 252598831 }}

The SC-FAs that activate FFAR3 include proprionic, butyric, acetic,{{cite journal | vauthors = Kuwahara A, Kuwahara Y, Inui T, Marunaka Y | title = Regulation of Ion Transport in the Intestine by Free Fatty Acid Receptor 2 and 3: Possible Involvement of the Diffuse Chemosensory System | journal = International Journal of Molecular Sciences | volume = 19 | issue = 3 | page = 735 | date = March 2018 | pmid = 29510573 | pmc = 5877596 | doi = 10.3390/ijms19030735 | doi-access = free }} valeric caproic,{{cite journal | vauthors = Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M | title = Free Fatty Acid Receptors in Health and Disease | journal = Physiological Reviews | volume = 100 | issue = 1 | pages = 171–210 | date = January 2020 | pmid = 31487233 | doi = 10.1152/physrev.00041.2018 | s2cid = 201845937 | doi-access = free }} and formic acids.{{cite journal | vauthors = Zhang D, Jian YP, Zhang YN, Li Y, Gu LT, Sun HH, Liu MD, Zhou HL, Wang YS, Xu ZX | title = Short-chain fatty acids in diseases | journal = Cell Communication and Signaling | volume = 21 | issue = 1 | article-number = 212 | date = August 2023 | pmid = 37596634 | pmc = 10436623 | doi = 10.1186/s12964-023-01219-9 | doi-access = free }} (Confusingly, butyric acid also activates hydroxycarboxylic acid receptor 2 and β-hydroxybutyric acid has been reported to stimulate or inhibit FFAR3.{{cite journal | vauthors = Won YJ, Lu VB, Puhl HL, Ikeda SR | title = β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3 | journal = The Journal of Neuroscience | volume = 33 | issue = 49 | pages = 19314–19325 | date = December 2013 | pmid = 24305827 | pmc = 3850046 | doi = 10.1523/JNEUROSCI.3102-13.2013 }}) FFAR2 is activated by many of these same SC-FAs but differs from FFAR3 in its relative binding affinities for them. In humans, the binding affinity ranking of FFAR3 is: propionic = butyric = valeric > acetic > formic acids (acetic and formic acids have very low binding affinities for, and therefore must be at extremely high levels to activate, FFAR3); FFAR2's relative binding affinity ranking for these SC-FAs is: acetic = propionic > butyric > valeric = formic acids. AR420626 (a derivative of an older compound 1-MCPC){{cite journal | vauthors = Christiansen CB, Gabe MB, Svendsen B, Dragsted LO, Rosenkilde MM, Holst JJ | title = The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 315 | issue = 1 | pages = G53–G65 | date = July 2018 | pmid = 29494208 | doi = 10.1152/ajpgi.00346.2017 | s2cid = 3633401 | doi-access = free }} has been reported to be a selective activator of FFAR3{{cite journal | vauthors = Mikami D, Kobayashi M, Uwada J, Yazawa T, Kamiyama K, Nishimori K, Nishikawa Y, Nishikawa S, Yokoi S, Taniguchi T, Iwano M | title = AR420626, a selective agonist of GPR41/FFA3, suppresses growth of hepatocellular carcinoma cells by inducing apoptosis via HDAC inhibition | journal = Therapeutic Advances in Medical Oncology | volume = 12 | issue = | pages = 1758835920913432 | date = 2020 | pmid = 33014144 | pmc = 7517987 | doi = 10.1177/1758835920913432 }} but has also been reported to inhibit the activation of FFAR3. Its actions require further characterizations. AR399519 and CF3-MQC have been reported to inhibit the activation of mouse FFAR3; the actions of these agents also require further characterizations.

Studies have shown that Ffar3 gene knockout mice fed a high fat diet have significant increases in their food intake and body weights compared to wild-type (i.e., genetically unaltered) mice. These and other studies in animals suggest that the activation of FFAR3 and FFAR2 on L cells by SC-FAs triggers the release of PYY and GLP-1, both of which, among various other activities, inhibit gastric emptying and thereby suppress appetite and the development of obesity. Further studies are needed to determine if FFAR3 plays a similar role in human satiety and obesity.

It should be noted, however, that Semaglutide, also called Wegovy, is a peptide with a modified GLP-1-like structure. It strongly stimulates GLP-1 receptors and thereby suppresses appetite and promotes weight loss in obese individuals.{{cite journal | vauthors = Iacobucci G | title = Appetite suppressant semaglutide is to be made available to treat obesity in England | journal = BMJ | volume = 380 | issue = | pages = 556 | date = March 2023 | pmid = 36889753 | doi = 10.1136/bmj.p556 | s2cid = 257379156 }}

Studies in mice have shown that activation of FFAR3 by short-chain fatty acids (SC-FAs) suppresses liver lipid synthesis, reduces triglyceride accumulation, and decreases liver weight in models of diet-induced obesity. Mice lacking the Ffar3 gene fail to exhibit these protective effects, suggesting a critical role for FFAR3 in preventing excessive hepatic fat accumulation. These findings support further research to determine whether FFAR3 functions similarly in humans and whether FFAR3 activators could be developed as potential treatments for human fatty liver diseases, including non-alcoholic fatty liver disease.{{cite journal | vauthors = Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F | title = From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites | journal = Cell | volume = 165 | issue = 6 | pages = 1332–1345 | date = June 2016 | pmid = 27259147 | doi = 10.1016/j.cell.2016.05.041 | s2cid = 8562345 | doi-access = free }}

In contrast to previous studies, a recent study of streptozotocin-induced and high-fat diet-induced murine models of diabetes found that the FFAR3-activating drug, AR420626, increased blood plasma insulin levels and stimulated skeletal muscle to take up glucose and thereby improved glucose tolerance test results.{{cite journal | vauthors = Lee DH, Heo KS, Myung CS | title = Gα_i -coupled GPR41 activation increases Ca²⁺ influx in C2C12 cells and shows a therapeutic effect in diabetic animals | journal = Obesity | volume = 31 | issue = 7 | pages = 1871–1883 | date = July 2023 | pmid = 37309717 | doi = 10.1002/oby.23786 | s2cid = 259147907 }}

Other recent studies have reported that activated FFAR3 may reduce, increase, or have little effect on insulin secretion depending on 1) the levels of ambient glucose and FFAR3 activators studied, (2) human or animal species studied, (3) age of the animals studied, and (4) variations in the proportions of alpha, beta, and delta cells in the pancreatic islets of humans. The role of FFAR3 in human as well as animal models of insulin secretion and diabetes requires further studies.

In a model where FFAR2 and FFAR3 were both deleted, these animals had an exaggerated response to hypertension, with higher fibrosis in the kidney; this was explained by a breakdown in the gut epithelial barrier and activation of the immune system via LPS/TLR4 binding.{{cite journal | vauthors = R Muralitharan R, Zheng T, Dinakis E, Xie L, Barbaro-Wahl A, Jama HA, Nakai M, Paterson M, Leung KC, McArdle Z, Mirabito Colafella K, Johnson C, Qin W, Salimova E, Bitto NJ, Kaparakis-Liaskos M, Kaye DM, O'Donnell JA, Mackay CR, Marques FZ | title = Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension | journal = Circulation Research | volume = 136 | issue = 4 | pages = e20–e33 | date = February 2025 | pmid = 39840468 | doi = 10.1161/CIRCRESAHA.124.325770 }}

Studies in humans have found that individuals undergoing hemodialysis using dialysis solutions that contain acetic acid often develop hypotension; the role of FFAR3 in this response, if any, was not investigated. A study of 69 individuals (55.1% women, mean age 59.8 years) found that arterial stiffness was associated with lower levels of FFAR3 and FFAR2 in circulating blood immune cells (particularly regulatory T cells which are known to be protective in murine models of hypertension{{cite journal | vauthors = R Muralitharan R, Marques FZ | title = Diet-related gut microbial metabolites and sensing in hypertension | journal = Journal of Human Hypertension | volume = 35 | issue = 2 | pages = 162–169 | date = February 2021 | pmid = 32733062 | doi = 10.1038/s41371-020-0388-3 | s2cid = 220881080 }}).{{cite journal | vauthors = Dinakis E, Nakai M, Gill PA, Yiallourou S, Sata Y, Muir J, Carrington M, Head GA, Kaye DM, Marques FZ | title = The Gut Microbiota and Their Metabolites in Human Arterial Stiffness | journal = Heart, Lung & Circulation | volume = 30 | issue = 11 | pages = 1716–1725 | date = November 2021 | pmid = 34452845 | doi = 10.1016/j.hlc.2021.07.022 | s2cid = 237340692 | url = https://discovery.ucl.ac.uk/id/eprint/10134898/1/The%20Gut%20Microbiota%20and%20Their%20Metabolites%20in%20Human%20Arterial%20Stiffness.pdf }}

Overall, the mouse studies suggest that FFAR3 contributes to suppressing hypertension and its subsequent effects on the heart in mice and that SC-FA-activated FFAR3 and/or FFAR2 may have vasodilatory actions and thereby suppress the development of hypertension and hypertension-induced arterial stiffness in humans. Further studies in humans are needed to investigate the latter possibilities.

Asthma may be atopic (i.e., symptoms triggered by allergens) or non-atopic (i.e., symptoms triggered by non-allergenic factors such as cold air). The studies reported here relate to allergen-induced asthma. Mice fed a diet that lowers their SC-FAs levels and then given intranasal injections of dust mite extract developed dust mite allergy asthma reactions to the injections. Their respiratory tract airways had increased numbers of eosinophils and goblet cells as well as excessive levels of mucus; their lung tissue levels of interleukin-4, interleukin-5, interleukin-13, and interleukin-17A and serum immunoglobulin E levels were elevated; and their airway resistance response to a bronchial challenge test was high. In contrast, mice fed a diet that increased their SC-FAs levels developed less of these responses to the extract. Furthermore, mice on the SC-FA lowering diet that were given propionic acid also had far less of these responses to the mite extract. And, Ffar3 (but not Ffar2) gene knockout mice on the low SF-FA diet did not show rises in their lung airway eosinophil levels in response to the mite extract (this was the only parameter of asthma reported in the knockout studies). These finding implicate propionic acid and FFAR3 in the suppression of asthma allergic reactions to mite extract in mice.{{cite journal | vauthors = Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ | title = Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis | journal = Nature Medicine | volume = 20 | issue = 2 | pages = 159–166 | date = February 2014 | pmid = 24390308 | doi = 10.1038/nm.3444 | s2cid = 35298402 | url = http://infoscience.epfl.ch/record/196353 }}

A second study investigated the effects that an inulin-rich diet (which raises bodily SC-FA levels) feed to rats had on their offsprings' development of asthma. Pregnant rats were feed a normal or inulin-rich diet for 1 week. Their offspring were injected with ovalbumin on days 21 and 29 after birth, 7 days later challenged with aerosolized ovalbumin, and on the next day examined for their responses to the aerosol. Compared to the offspring of mothers on a normal diet, the offspring of mothers on the inulin diet had lower levels of lung inflammatory cells, less histological evidence of allergic lung disease, lower lung tissue levels of immunoglobulin E, interleukin-4, and interleukin-17, and significantly elevated lung levels of FFAR3 (Lung FFAR2 levels were not significantly elevated). These results indicate that a diet promoting the production of SC-FAs in pregnant rats suppresses the development of asthmatic disease in their offspring; this suppression may involve FFAR3. In a similar study, newborn mice were feed breast milk from mothers who had drunk pure water or water containing a SC-FA. After 3 weeks, the newborns were weaned off the mothers' milk, feed plain water, and 3 weeks thereafter sensitized to and challenged by injection of mite extract into their tracheas. Mothers who drank pure water or water laced with acetic or butyric acid and sensitized to the mite extract had asthma signs after challenge with the extract whereas mothers who drank propionic acid-laced water had far less of these signs. Furthermore, Ffar3 gene knockout mothers who drank propionic acid-laced water and then sensitized to the mite extract had asthma signs similar to these in wild type mothers challenged with the extract. The study also found that the offspring of mothers who drank propionic acid-laced water had fewer eosinophils and T helper cells in their airways than the offsprings of mothers who drank pure water, acetic acid-laced water, or butyric acid-laced water. Propionic acid-laced water did not suppress the development of asthma in Ffar3 gene knockout offsprings. These results indicate that ingestion of propionic acid, but not acetic or butyric acid, suppresses the development of allergic asthma in adult as well as newborn rats and does so by a FFAR3-dependent mechanism. The studies also indicate that the milk of pregnant rats who consumed propionic acid-laced but not those who drank pure water reduced the susceptibility of newborn rats to developing allergic asthma by a mechanism dependent on FFAR3 in the mothers as well as the offsprings. These findings support further studies to determine if propionic acid or other FFAR3 activators would be useful for preventing and/or treating asthma in humans.{{cite journal | vauthors = Ito T, Nakanishi Y, Shibata R, Sato N, Jinnohara T, Suzuki S, Suda W, Hattori M, Kimura I, Nakano T, Yamaide F, Shimojo N, Ohno H | title = The propionate-GPR41 axis in infancy protects from subsequent bronchial asthma onset | journal = Gut Microbes | volume = 15 | issue = 1 | pages = 2206507 | date = 2023 | pmid = 37131293 | pmc = 10158560 | doi = 10.1080/19490976.2023.2206507 }}

A study of humans living on European farms or in non-farm rural areas reported that the fecal levels of butyric but not acetic acid in 12 month old children who had not develop asthma by the time they entered the first year of school were significantly higher than these levels in children who did develop asthma by the school entry age.{{cite journal | vauthors = Depner M, Taft DH, Kirjavainen PV, Kalanetra KM, Karvonen AM, Peschel S, Schmausser-Hechfellner E, Roduit C, Frei R, Lauener R, Divaret-Chauveau A, Dalphin JC, Riedler J, Roponen M, Kabesch M, Renz H, Pekkanen J, Farquharson FM, Louis P, Mills DA, von Mutius E, Ege MJ | title = Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma | journal = Nature Medicine | volume = 26 | issue = 11 | pages = 1766–1775 | date = November 2020 | pmid = 33139948 | doi = 10.1038/s41591-020-1095-x | hdl-access = free | s2cid = 226244474 | hdl = 2164/16359 }} A study conducted in Canada reported that the levels of fecal acetic acid (but not butyric or propionic acid) were lower in 3 month old human infants who were predicted to have asthma by school age (based on a Phylogenetic Investigation of Communities by Reconstruction of Unobserved States prediction algorithm) compared to infants predicted not to do so.{{cite journal | vauthors = Arrieta MC, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, Kuzeljevic B, Gold MJ, Britton HM, Lefebvre DL, Subbarao P, Mandhane P, Becker A, McNagny KM, Sears MR, Kollmann T, Mohn WW, Turvey SE, Finlay BB | title = Early infancy microbial and metabolic alterations affect risk of childhood asthma | journal = Science Translational Medicine | volume = 7 | issue = 307 | pages = 307ra152 | date = September 2015 | pmid = 26424567 | doi = 10.1126/scitranslmed.aab2271 | s2cid = 206687974 | doi-access = free }} Finally, a study conducted in Japan found that the fecal levels of propionic but not acetic or butyric acid trended lower in 1 month old human infants that developed asthma by age 5 than in infants that did not develop asthma. The fecal levels of propionic as well acetic and butyric acid obtained from 1 week-, 1 year, and 5-year-old infants did not show this trend. The different SC-FA implicated in suppressing asthma in these three studies may reflect dietary or other differences between the populations of the three countries. In all events, the studies allow that, based on rodent studies, FFAR3 may mediate these SG-FA actions and, based on human studies, SC-FAs may act to suppress, or at least delay) the onset of, asthma in children Further studies are needed to determine if FFAR3 is involved in the apparent actions of the cited SC-FAs in the development of asthma in children.

; Agonists

• AR420626{{cite journal | vauthors = Hudson BD, Christiansen E, Murdoch H, Jenkins L, Hansen AH, Madsen O, Ulven T, Milligan G | title = Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands | journal = Molecular Pharmacology | volume = 86 | issue = 2 | pages = 200–210 | date = August 2014 | pmid = 24870406 | doi = 10.1124/mol.114.093294 }}

; Antagonists

• β-Hydroxybutyric acid (endogenous){{cite journal | vauthors = Ulven T | title = Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets | journal = Frontiers in Endocrinology | volume = 3 | pages = 111 | date = 2012 | pmid = 23060857 | pmc = 3462324 | doi = 10.3389/fendo.2012.00111 | doi-access = free }}
• AR399519{{cite journal | vauthors = Christiansen CB, Gabe MB, Svendsen B, Dragsted LO, Rosenkilde MM, Holst JJ | title = The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 315 | issue = 1 | pages = G53–G65 | date = July 2018 | pmid = 29494208 | doi = 10.1152/ajpgi.00346.2017 }}
• CF3-MQC{{cite journal | vauthors = Said H, Akiba Y, Narimatsu K, Maruta K, Kuri A, Iwamoto KI, Kuwahara A, Kaunitz JD | title = FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats | journal = Digestive Diseases and Sciences | volume = 62 | issue = 8 | pages = 1944–1952 | date = August 2017 | pmid = 28523577 | pmc = 5511769 | doi = 10.1007/s10620-017-4600-4 }}

• Free fatty acid receptor
• Disorders treated by probiotics
• Disorders treated by prebiotics

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{{G protein-coupled receptors}}