Journal articles: 'FFA3'

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Priyadarshini, Medha, Guadalupe Navarro, and Brian T. Layden. "Gut Microbiota: FFAR Reaching Effects on Islets." Endocrinology 159, no. 6 (May 4, 2018): 2495–505. http://dx.doi.org/10.1210/en.2018-00296.

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Abstract The G protein–coupled receptors, free fatty acid (FFA) receptors 2 and 3 (FFA2 and FFA3), belonging to the free fatty acid receptor (FFAR) class, sense a distinct class of nutrients, short chain fatty acids (SCFAs). These receptors participate in both immune and metabolic regulation. The latter includes a role in regulating secretion of metabolic hormones. It was only recently that their role in pancreatic β cells was recognized; these receptors are known now to affect not only insulin secretion but also β-cell survival and proliferation. These observations make them excellent potential therapeutic targets in type 2 diabetes. Moreover, expression on both immune and β cells makes these receptors possible targets in type 1 diabetes. Furthermore, SCFAs are generated by gut microbial fermentative activity; therefore, signaling by FFA2 and FFA3 represents an exciting novel link between the gut microbiota and the β cells. This review enumerates the role of these receptors in β cells revealed so far and discusses possible roles in clinical translation.

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Schmidt, Johannes, Nicola J. Smith, Elisabeth Christiansen, Irina G. Tikhonova, Manuel Grundmann, Brian D. Hudson, Richard J. Ward, et al. "Selective Orthosteric Free Fatty Acid Receptor 2 (FFA2) Agonists." Journal of Biological Chemistry 286, no. 12 (January 10, 2011): 10628–40. http://dx.doi.org/10.1074/jbc.m110.210872.

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Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane receptor for short-chain fatty acids (SCFAs) that is implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency for FFA2 and can hence be considered as highly potent given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2-selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids was examined using holistic, label-free dynamic mass redistribution technology for primary screening and the receptor-proximal G protein [35S]guanosine 5′-(3-O-thio)triphosphate activation, inositol phosphate, and cAMP accumulation assays for hit confirmation. Structure-activity relationship analysis allowed formulation of a general rule to predict selectivity for small carboxylic acids at the orthosteric binding site where ligands with substituted sp3-hybridized α-carbons preferentially activate FFA3, whereas ligands with sp2- or sp-hybridized α-carbons prefer FFA2. The orthosteric binding mode was verified by site-directed mutagenesis: replacement of orthosteric site arginine residues by alanine in FFA2 prevented ligand binding, and molecular modeling predicted the detailed mode of binding. Based on this, selective mutation of three residues to their non-conserved counterparts in FFA3 was sufficient to transfer FFA3 selectivity to FFA2. Thus, selective activation of FFA2 via the orthosteric site is achievable with rather small ligands, a finding with significant implications for the rational design of therapeutic compounds selectively targeting the SCFA receptors.

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Bisenieks, Egils, Brigita Vigante, Ramona Petrovska, Baiba Turovska, Ruslan Muhamadejev, Vitalijs Soloduns, Astrida Velena, et al. "The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A." Pharmaceuticals 14, no. 10 (September 28, 2021): 987. http://dx.doi.org/10.3390/ph14100987.

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The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have been synthesized in order to characterise their pleiotropic, multitarget activity on the FFA3/GPR41, FFA2/GPR43, and HCA2/GPR109A receptors. Hexahydroquinoline derivatives have been known to exhibit characteristic activity as FFA3/GPR41 ligands, but during this study we observed their impact on FFA2/GPR43 and HCA2/GPR109A receptors as well as their electron-donating activity. Oxopyranopyrimidine and thioxopyranopyrimidine type compounds have been studied as ligands of the HCA2/GPR109A receptor; nevertheless, they exhibited equal or higher activity towards FFA3/GPR41 and FFA2/GPR43 receptors. S-Alkyl derivatives of pyranopyrimidines that have not yet been studied as ligands of GPCRs were more active towards HCA2/GPR109A and FFA3/GPR41 receptors than towards FFA2/GPR43. Representative compounds from each synthesized series were able to decrease the lipopolysaccharide-induced gene expression and secretion of proinflammatory cytokines (IL-6, TNF-α) and of a chemokine (MCP-1) in THP-1 macrophages, resembling the effect of HCA2/GPR109A ligand niacin and the endogenous ligand propionate. This study revealed groups of compounds possessing multitarget activity towards several receptors. The obtained data could be useful for further development of multitarget ligands.

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Gough, Sophie, Brian Layden, Chioma Nnyamah, Medha Priyadarshini, Barton Wicksteed, and Kristen Lednovich. "OR23-4 Intestinal FFA2 and FFA3 Mediate Obesogenic Effects in Mice on a Western Diet." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A19. http://dx.doi.org/10.1210/jendso/bvac150.040.

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Abstract Free fatty acid receptor 2 and free fatty acid receptor 3 (FFA2/3) are two highly similar G protein-coupled receptors belonging to the free fatty acid receptor family. Their ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA2/3 are broadly expressed in a multitude of tissues including the intestine, pancreas, adipose and central nervous system, where they contribute to metabolic homeostasis via a summation of tissue-specific effects. Consequently, FFA2/3 have been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. Both FFA2 and FFA3 are highly expressed within the intestinal epithelium – the major site of SCFA generation – and have been identified in hormone-secreting enteroendocrine cells as well as intestinal epithelial cells. However, due conflicting data, the respective roles of FFA2/3 within the intestine and their effects on physiology and metabolism are still largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate their effects in the intestine. To overcome this challenge, we generated a novel intestine-specific knockout mouse model for FFA2 and FFA3 individually, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA2/3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA2 (Vil-FFA2) and Villin-Cre-FFA3 (Vil-FFA3) mice on standard chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Vil-FFA2 and Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "western diet." Mice were placed on either a low-fat control diet (CD) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. We found that both Vil-FFA2 and Vil-FFA3 mouse strains were largely protected from diet-induced obesity and had significantly lower fat mass as well as adipose hypertrophy. Additionally, both mouse strains had reduced intestinal inflammation and improved glucose homeostasis. These differences were driven by lower food intake in the Vil-FFA2 strain only. Our findings suggest a novel role of FFA2/3 in mediating the metabolic consequences of a western diet – a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA2/3 in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia. Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.

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Priyadarshini, Medha, Connor Cole, Gautham Oroskar, Anton E. Ludvik, Barton Wicksteed, Congcong He, and Brian T. Layden. "Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 4 (April 1, 2020): R691—R700. http://dx.doi.org/10.1152/ajpregu.00128.2019.

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The free fatty acid receptor 3 (FFA3) is a nutrient sensor of gut microbiota-generated nutrients, the short-chain fatty acids. Previously, we have shown that FFA3 is expressed in β-cells and inhibits islet insulin secretion ex vivo. Here, we determined the physiological relevance of the above observation by challenging wild-type (WT) and FFA3 knockout (KO) male mice with 1) hyperglycemia and monitoring insulin response via highly sensitive hyperglycemic clamps, 2) dietary high fat (HF), and 3) chemical-induced diabetes. As expected, FFA3 KO mice exhibited significantly higher insulin secretion and glucose infusion rate in hyperglycemic clamps. Predictably, under metabolic stress induced by HF-diet feeding, FFA3 KO mice exhibited less glucose intolerance compared with the WT mice. Moreover, similar islet architecture and β-cell area in HF diet-fed FFA3 KO and WT mice was observed. Upon challenge with streptozotocin (STZ), FFA3 KO mice initially exhibited a tendency for an accelerated incidence of diabetes compared with the WT mice. However, this difference was not maintained. Similar glycemia and β-cell mass loss was observed in both genotypes 10 days post-STZ challenge. Higher resistance to STZ-induced diabetes in WT mice could be due to higher basal islet autophagy. However, this difference was not protective because in response to STZ, similar autophagy induction was observed in both WT and FFA3 KO islets. These data demonstrate that FFA3 plays a role in modulating insulin secretion and β-cell response to stressors. The β-cell FFA3 and autophagy link warrant further research.

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Zamarbide, Marta, Eva Martinez-Pinilla, Francisco Gil-Bea, Masashi Yanagisawa, Rafael Franco, and Alberto Perez-Mediavilla. "Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer’s Disease Mouse Model." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3533. http://dx.doi.org/10.3390/ijms23073533.

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The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APPswe mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R−/−/APPswe, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R−/−/APPswe mice do not have the characteristic memory impairment of 12-month-old APPswe mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer’s disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.

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Lednovich, Kristen Roan, Sophie Gough, Medha Priyadarshini, and Brian T. Layden. "Loss of Intestine-Specific FFA3 Has Protective Effects Against Diet-Induced Obesity and Hyperglycemia in Mice on a Western Diet." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A441. http://dx.doi.org/10.1210/jendso/bvab048.901.

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Abstract Free fatty acid receptor 3 (FFA3) is a recently-deorphaned G protein-coupled receptor belonging to the free fatty acid receptor family. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA3 is broadly expressed in a multitude of tissues including the intestine, pancreas, and central nervous system, and is thought to contribute to metabolic homeostasis via a summation of its tissue-specific effects. Consequently, FFA3 has been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. FFA3 is highly expressed in enteroendocrine cells (EECs) within the intestinal epithelium - the major site of SCFA generation - and is hypothesized to play a role in the secretion of postprandial incretin hormones, which are a group of specialized gut peptides that regulate a variety of metabolic and digestive functions following a meal. However, due to a paucity of data, the role of FFA3 within the intestine and its effects on physiology and metabolism is largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate its effects in EECs. To overcome this challenge, we have generated a novel intestine-specific knockout mouse model for FFA3, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA3 mice on normal chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Villin-Cre-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar “western diet.” Mice were placed on either normal chow (NC) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. Our data reveals that Villin-Cre-FFA3 mice on WD, but not NC, were protected from diet-induced metabolic dysfunction, and displayed significantly lower levels of fat mass as well as modestly improved glycemic control. Our findings suggest a novel role of FFA3 in mediating the metabolic consequences of a western diet - a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA3 in both glucose and lipid metabolism, and further suggest the receptor’s role in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia.

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Villa, Stephanie R., Rama K. Mishra, Joseph L. Zapater, Medha Priyadarshini, Annette Gilchrist, Helena Mancebo, Gary E. Schiltz, and Brian T. Layden. "Homology modeling of FFA2 identifies novel agonists that potentiate insulin secretion." Journal of Investigative Medicine 65, no. 8 (August 7, 2017): 1116–24. http://dx.doi.org/10.1136/jim-2017-000523.

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Critical aspects of maintaining glucose homeostasis in the face of chronic insulin resistance and type 2 diabetes (T2D) are increased insulin secretion and adaptive expansion of beta cell mass. Nutrient and hormone sensing G protein-coupled receptors are important mediators of these properties. A growing body of evidence now suggests that the G protein-coupled receptor, free fatty acid receptor 2 (FFA2), is capable of contributing to the maintenance of glucose homeostasis by acting at the pancreatic beta cell as well as at other metabolically active tissues. We have previously demonstrated that Gαq/11-biased agonism of FFA2 can potentiate glucose stimulated insulin secretion (GSIS) as well as promote beta cell proliferation. However, the currently available Gαq/11-biased agonists for FFA2 exhibit low potency, making them difficult to examine in vivo. This study sought to identify Gαq/11-biased FFA2-selective agonists with potent GSIS-stimulating effects. To do this, we generated an FFA2 homology model that was used to screen a library of 10 million drug-like compounds. Although FFA2 and the related short chain fatty acid receptor FFA3 share 52% sequence similarity, our virtual screen identified over 50 compounds with predicted selectivity and increased potency for FFA2 over FFA3. Subsequent in vitro calcium mobilization assays and GSIS assays resulted in the identification of a compound that can potentiate GSIS via activation of Gαq/11with 100-fold increased potency compared with previously described Gαq/11-biased FFA2 agonists. These methods and findings provide a foundation for future discovery efforts to identify biased FFA2 agonists as potential T2D therapeutics.

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Lednovlch, Kristen R., Sophie Gough, Medha Priyadarshini, and Brian Layden. "Tu1952 DEFINING THE ROLE OF INTESTINE-SPECIFIC FFA2 AND FFA3 IN HORMONAL SECRETION." Gastroenterology 158, no. 6 (May 2020): S—1231. http://dx.doi.org/10.1016/s0016-5085(20)33739-2.

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Mikami, Daisuke, Mamiko Kobayashi, Junsuke Uwada, Takashi Yazawa, Kazuko Kamiyama, Kazuhisa Nishimori, Yudai Nishikawa, et al. "AR420626, a selective agonist of GPR41/FFA3, suppresses growth of hepatocellular carcinoma cells by inducing apoptosis via HDAC inhibition." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592091343. http://dx.doi.org/10.1177/1758835920913432.

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Background: Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide and establishment of new chemotherapies for HCC is urgently needed. GPR41 [free fatty acid receptor 3 (FFA3)] is a G protein-coupled receptor for short chain fatty acids, including acetate, propionate, and butyrate. In our previous study, we showed that propionate enhances the cytotoxic effect of cisplatin in HCC cells and that this mechanism is dependent on inhibition of histone deacetylases (HDACs) via GPR41/FFA3. However, the antitumor action of GPR41/FFA3 has not been elucidated. Methods: In this study, we examined AR420626 as a GPR41-selective agonist in HepG2 and HLE cells. Nude mice were used for HepG2 xenograft studies. The apoptotic effect of AR420626 was evaluated using flow cytometry analysis. Expression of apoptosis-related proteins and HDACs was evaluated by Western immunoblot. Gene silencing of HDAC 3/5/7 and GPR41 was performed using small interfering RNA. Expression of TNF-α mRNA was evaluated by TaqMan real-time polymerase chain reaction. Results: We found that AR420626, a selective GPR41/FFA3 agonist, suppressed growth of HepG2 xenografts and inhibited proliferation of HCC cells by inducing apoptosis. AR420626 induced proteasome activation through mTOR phosphorylation, which reduced HDAC proteins, and then increased expression of TNF-α. Conclusion: AR420626, a selective GPR41/FFA3 agonist, may be a candidate as a therapeutic agent for HCC.

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Kaji, Izumi, Yasutada Akiba, Jonathan D. Kaunitz, Shin-ichiro Karaki, and Atsukazu Kuwahara. "Su1745 Differential Expression of Short-Chain Fatty Acid Receptor FFA2 and FFA3 in Foregut." Gastroenterology 142, no. 5 (May 2012): S—494. http://dx.doi.org/10.1016/s0016-5085(12)61887-3.

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Milligan, Graeme, Leigh A. Stoddart, and Nicola J. Smith. "Agonism and allosterism: the pharmacology of the free fatty acid receptors FFA2 and FFA3." British Journal of Pharmacology 158, no. 1 (September 2009): 146–53. http://dx.doi.org/10.1111/j.1476-5381.2009.00421.x.

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Mikami, Daisuke, Mamiko Kobayashi, Junsuke Uwada, Takashi Yazawa, Kazuko Kamiyama, Kazuhisa Nishimori, Yudai Nishikawa, et al. "Short-chain fatty acid mitigates adenine-induced chronic kidney disease via FFA2 and FFA3 pathways." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1865, no. 6 (June 2020): 158666. http://dx.doi.org/10.1016/j.bbalip.2020.158666.

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Tang, Cong, Kashan Ahmed, Andreas Gille, Shun Lu, Hermann-Josef Gröne, Sorin Tunaru, and Stefan Offermanns. "Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes." Nature Medicine 21, no. 2 (January 12, 2015): 173–77. http://dx.doi.org/10.1038/nm.3779.

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Vaziri, Nosratola D., Ane C. F. Nunes, Hyder Said, Mahyar Khazaeli, Han Liu, Yitong Zhao, Wanghui Jing, Kyle Cogburn, Leila Alikhani, and Wei Ling Lau. "Route of intestinal absorption and tissue distribution of iron contained in the novel phosphate binder ferric citrate." Nephrology Dialysis Transplantation 35, no. 7 (June 8, 2020): 1136–44. http://dx.doi.org/10.1093/ndt/gfaa053.

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Abstract Background Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here. Methods Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions. Results CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon’s epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration. Conclusion Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

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Lymperopoulos, Anastasios, Malka S. Suster, and Jordana I. Borges. "Short-Chain Fatty Acid Receptors and Cardiovascular Function." International Journal of Molecular Sciences 23, no. 6 (March 18, 2022): 3303. http://dx.doi.org/10.3390/ijms23063303.

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Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.

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Kaji, Izumi, Yasutada Akiba, Kazuyuki Narimatsu, and Jonathan D. Kaunitz. "Tu1403 Neural FFA3 Activation Inversely Regulates Cholinergic Secretory Function in Rat Proximal Colon." Gastroenterology 148, no. 4 (April 2015): S—880. http://dx.doi.org/10.1016/s0016-5085(15)32990-5.

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Hudson, Brian D., Irina G. Tikhonova, Sunil K. Pandey, Trond Ulven, and Graeme Milligan. "Extracellular Ionic Locks Determine Variation in Constitutive Activity and Ligand Potency between Species Orthologs of the Free Fatty Acid Receptors FFA2 and FFA3." Journal of Biological Chemistry 287, no. 49 (October 12, 2012): 41195–209. http://dx.doi.org/10.1074/jbc.m112.396259.

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Freitas, Raquel D. S., Thaís C. Muradás, Ana Paula A. Dagnino, Fernanda L. Rost, Kesiane M. Costa, Gianina T. Venturin, Samuel Greggio, Jaderson C. da Costa, and Maria M. Campos. "Targeting FFA1 and FFA4 receptors in cancer-induced cachexia." American Journal of Physiology-Endocrinology and Metabolism 319, no. 5 (November 1, 2020): E877—E892. http://dx.doi.org/10.1152/ajpendo.00509.2019.

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Free fatty acid (FFA) receptors FFA1 and FFA4 are omega-3 molecular targets in metabolic diseases; however, their function in cancer cachexia remains unraveled. We assessed the role of FFA1 and FFA4 receptors in the mouse model of cachexia induced by Lewis lung carcinoma (LLC) cell implantation. Naturally occurring ligands such as α-linolenic acid (ALA) and docosahexaenoic acid (DHA), the synthetic FFA1/FFA4 agonists GW9508 and TUG891, or the selective FFA1 GW1100 or FFA4 AH7614 antagonists were tested. FFA1 and FFA4 expression and other cachexia-related parameters were evaluated. GW9508 and TUG891 decreased tumor weight in LLC-bearing mice. Regarding cachexia-related end points, ALA, DHA, and the preferential FFA1 agonist GW9508 rescued body weight loss. Skeletal muscle mass was reestablished by ALA treatment, but this was not reflected in the fiber cross-sectional areas (CSA) measurement. Otherwise, TUG891, GW1100, or AH7614 reduced the muscle fiber CSA. Treatments with ALA, GW9508, GW1100, or AH7614 restored white adipose tissue (WAT) depletion. As for inflammatory outcomes, ALA improved anemia, whereas GW9508 reduced splenomegaly. Concerning behavioral impairments, ALA and GW9508 rescued locomotor activity, whereas ALA improved motor coordination. Additionally, DHA improved grip strength. Notably, GW9508 restored abnormal brain glucose metabolism in different brain regions. The GW9508 treatment increased leptin levels, without altering uncoupling protein-1 downregulation in visceral fat. LLC-cachectic mice displayed FFA1 upregulation in subcutaneous fat, but not in visceral fat or gastrocnemius muscle, whereas FFA4 was unaltered. Overall, the present study shed new light on FFA1 and FFA4 receptors’ role in metabolic disorders, indicating FFA1 receptor agonism as a promising strategy in mitigating cancer cachexia.

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Al Mahri, Saeed, Shuja Shafi Malik, Maria Al Ibrahim, Esraa Haji, Ghida Dairi, and Sameer Mohammad. "Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook." Cells 11, no. 4 (February 21, 2022): 750. http://dx.doi.org/10.3390/cells11040750.

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Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes.

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Patti, Angelo Maria, Rosaria Vincenza Giglio, Nikolaos Papanas, Dragos Serban, Anca Pantea Stoian, Kalliopi Pafili, Khalid Al Rasadi, et al. "Experimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes." Medicina 58, no. 1 (January 11, 2022): 109. http://dx.doi.org/10.3390/medicina58010109.

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The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM. To comprehensively review the available evidence for the potential role of FFA receptor agonists in the treatment of T2DM, we performed an electronic database search assessing the association between FFAs, T2DM, inflammation, and incretins. Evidence indicates that FFA1-4 agonism increases insulin sensitivity, induces body mass loss, reduces inflammation, and has beneficial metabolic effects. There is a strong inter-relationship between FFAs and incretins. FFA receptor agonism represents a potential target for the treatment of T2DM and may provide an avenue for the management of cardiometabolic risk in susceptible individuals. Further research promises to shed more light on this emerging topic.

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Grundmann, Manuel, Eckhard Bender, Jens Schamberger, and Frank Eitner. "Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators." International Journal of Molecular Sciences 22, no. 4 (February 10, 2021): 1763. http://dx.doi.org/10.3390/ijms22041763.

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The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

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Kaji, Izumi, Yasutada Akiba, Takafumi Furuyama, and Jonathan D. Kaunitz. "Sa1705 FFA3 Activation Inhibits Nicotine-induced Secretion and Motility via Enteric Nervous Reflex in Rat Proximal Colon." Gastroenterology 150, no. 4 (April 2016): S352. http://dx.doi.org/10.1016/s0016-5085(16)31234-3.

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Kaji, Izumi, Yasutada Akiba, Kohtarou Konno, Masahiko Watanabe, Shunsuke Kimura, Toshihiko Iwanaga, Ayaka Kuri, Ken-ichi Iwamoto, Atsukazu Kuwahara, and Jonathan D. Kaunitz. "Neural FFA3 activation inversely regulates anion secretion evoked by nicotinic ACh receptor activation in rat proximal colon." Journal of Physiology 594, no. 12 (March 20, 2016): 3339–52. http://dx.doi.org/10.1113/jp271441.

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Said, Hyder, Yasutada Akiba, Kazuyuki Narimatsu, Koji Maruta, Ayaka Kuri, Ken-ichi Iwamoto, Atsukazu Kuwahara, and Jonathan D. Kaunitz. "FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats." Digestive Diseases and Sciences 62, no. 8 (May 18, 2017): 1944–52. http://dx.doi.org/10.1007/s10620-017-4600-4.

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Kaji, Izumi, Yuki Shimizu, Junki Miyamoto, Ikuo Kimura, and Jonathan D. Kaunitz. "Sa1214 - The Anti-Diarrheal Effect of Free Fatty Acid Receptor (Ffa)3 Agonist Ar420626 is Independent of Ffa3 or Pyy Signaling in a Murine Model of Irritable Bowel Syndrome." Gastroenterology 154, no. 6 (May 2018): S—279—S—280. http://dx.doi.org/10.1016/s0016-5085(18)31295-2.

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Said, Hyder, Yasutada Akiba, Izumi Kaji, and Jonathan D. Kaunitz. "683 Selective FFA3 Agonists Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats." Gastroenterology 150, no. 4 (April 2016): S141. http://dx.doi.org/10.1016/s0016-5085(16)30574-1.

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Kimura, Ikuo, Atsuhiko Ichimura, Ryuji Ohue-Kitano, and Miki Igarashi. "Free Fatty Acid Receptors in Health and Disease." Physiological Reviews 100, no. 1 (January 1, 2020): 171–210. http://dx.doi.org/10.1152/physrev.00041.2018.

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Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.

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Won, Y. J., V. B. Lu, H. L. Puhl, and S. R. Ikeda. "-Hydroxybutyrate Modulates N-Type Calcium Channels in Rat Sympathetic Neurons by Acting as an Agonist for the G-Protein-Coupled Receptor FFA3." Journal of Neuroscience 33, no. 49 (December 4, 2013): 19314–25. http://dx.doi.org/10.1523/jneurosci.3102-13.2013.

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Kytikova, O. Yu, T. P. Novgorodtseva, Yu K. Denisenko, M. V. Antonyuk, and T. A. Gvozdenko. "Medium and long chain free fatty acid receptors in the pathophysiology of respiratory diseases." Bulletin Physiology and Pathology of Respiration, no. 80 (July 16, 2021): 115–28. http://dx.doi.org/10.36604/1998-5029-2021-80-115-128.

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Chronic inflammatory diseases of the respiratory tract, including asthma and chronic obstructive pulmonary disease, are a global problem of our time due to the widespread prevalence and difficulty of controlling the course. The mechanism of chronic inflammation in the bronchopulmonary system is closely related to metabolic disorders of lipids and their derivatives. Lipids and their mediators play both a pro-inflammatory and anti-inflammatory role in chronic inflammatory bronchopulmonary pathology. In particular, free fatty acids (FFAs) perform important signaling and regu latory functions in the body, coordinating metabolic and immune relationships. The mechanism that potentially binds FFAs and inflammatory reactions involves the activation of their receptors (FFAR – free fatty acid receptor), which are expressed on the cells of the respiratory tract, as well as on nerve and immune cells. Currently, FFARs are considered attractive targets in the treatment of chronic bronchopulmonary pathology, since modulation of their activity through the use of alimentary polyunsaturated fatty acids (PUFA) can affect the activity and resolution of neuroimmune inflammation in the bronchopulmonary system. However, controversial issues regarding their effectiveness and dose standardization of PUFA continue to limit their widespread use. This review summarizes the literature data on the role of medium- and longchain FFAs in the body’s immunoregulation in normal conditions and in chronic bronchopulmonary pathology. Data on medium and long chain FFA receptors – FFAR1 and FFAR4, FFAR-mediated signaling pathways in the regulation of metabolism and immune responses are systematized. The perspective and complex issues of the use of fatty acids in the treatment of chronic bronchopulmonary pathology are discussed.

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Isobe, Junya, Shintarou Maeda, Yuuki Obata, Keito Iizuka, Yutaka Nakamura, Yumiko Fujimura, Tatsuki Kimizuka, et al. "Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon." International Immunology 32, no. 4 (December 20, 2019): 243–58. http://dx.doi.org/10.1093/intimm/dxz078.

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Abstract Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensal-bacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.

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Velasco, Cristina, Marta Conde-Sieira, Sara Comesaña, Mauro Chivite, Adrián Díaz-Rúa, Jesús M. Míguez, and José L. Soengas. "The long-chain fatty acid receptors FFA1 and FFA4 are involved in food intake regulation in fish brain." Journal of Experimental Biology 223, no. 17 (July 14, 2020): jeb227330. http://dx.doi.org/10.1242/jeb.227330.

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ABSTRACTWe hypothesized that the free fatty acid receptors FFA1 and FFA4 might be involved in the anorectic response observed in fish after rising levels of long-chain fatty acids (LCFAs) such as oleate. In one experiment we demonstrated that intracerebroventricular (i.c.v.) treatment of rainbow trout with FFA1 and FFA4 agonists elicited an anorectic response 2, 6 and 24 h after treatment. In a second experiment, the same i.c.v. treatment resulted after 2 h in an enhancement in the mRNA abundance of anorexigenic neuropeptides pomca1 and cartpt and a decrease in the values of orexigenic peptides npy and agrp1. These changes occurred in parallel with those observed in the mRNA abundance and/or protein levels of the transcription factors Creb, Bsx and FoxO1, protein levels and phosphorylation status of Ampkα and Akt, and mRNA abundance of plcb1 and itrp3. Finally, we assessed in a third experiment the response of all these parameters after 2 h of i.c.v. treatment with oleate (the endogenous ligand of both free fatty acid receptors) alone or in the presence of FFA1 and FFA4 antagonists. Most effects of oleate disappeared in the presence of FFA1 and FFA4 antagonists. The evidence obtained supports the involvement of FFA1 and FFA4 in fatty acid sensing in fish brain, and thus involvement in food intake regulation through mechanisms not exactly comparable (differential response of neuropeptides and cellular signalling) to those known in mammals.

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Christiansen, Elisabeth, Kenneth R. Watterson, Claire J. Stocker, Elena Sokol, Laura Jenkins, Katharina Simon, Manuel Grundmann, et al. "Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases." British Journal of Nutrition 113, no. 11 (April 28, 2015): 1677–88. http://dx.doi.org/10.1017/s000711451500118x.

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Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration–response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.

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Hori, Yasushi, Kazutoshi Nakamura, Masaharu Yamamoto, Kenji Shimada, Hiroto Nakadaira, Norio Shibuya, Kazuo Endoh, and Kazuei Ogoshi. "Determination of Free Fatty Acids in Human Bile by High-Performance Liquid Chromatography." Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 35, no. 2 (March 1998): 279–82. http://dx.doi.org/10.1177/000456329803500213.

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We developed a high-performance liquid chromatography (HPLC) method for free fatty acids (FFAs) analysis in bile. In this method, FFAs were extracted from bile in a single step using an Isolute™ ODS cartridge, derivatized with 9-anthryldiazomethane (ADAM). ADAM was chosen because of its high reactivity with carboxylic acid at room temperature. Then, HPLC was used for separating and quantifying FFAs. This method proved to be simple and time-saving. The mean recovery of FFA added to human gallbladder bile was 97.6%, and the detection limit was 100–250 pg. Using this method, we determined FFA concentrations in the gallbladder bile of 11 gallstone patients. The mean concentration of total FFA was 0.61 (SD = 0.41) mmol/L, and there was wide variation in the individual FFAs.

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Alharbi, Abdulrahman G., Andrew B. Tobin, and Graeme Milligan. "How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors." International Journal of Molecular Sciences 23, no. 20 (October 13, 2022): 12237. http://dx.doi.org/10.3390/ijms232012237.

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FFA1 and FFA4, two G protein-coupled receptors that are activated by long chain fatty acids, play crucial roles in mediating many biological functions in the body. As a result, these fatty acid receptors have gained considerable attention due to their potential to be targeted for the treatment of type-2 diabetes. However, the relative contribution of canonical G protein-mediated signalling versus the effects of agonist-induced phosphorylation and interactions with β-arrestins have yet to be fully defined. Recently, several reports have highlighted the ability of β-arrestins and GRKs to interact with and modulate different functions of both FFA1 and FFA4, suggesting that it is indeed important to consider these interactions when studying the roles of FFA1 and FFA4 in both normal physiology and in different disease settings. Here, we discuss what is currently known and show the importance of understanding fully how β-arrestins and GRKs regulate the function of long chain fatty acid receptors.

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Pilitsis, Julie G., William M. Coplin, Michael H. O'Regan, Jody M. Wellwood, Fernando G. Diaz, Marilynn R. Fairfax, Daniel B. Michael, and John W. Phillis. "Free fatty acids in human cerebrospinal fluid following subarachnoid hemorrhage and their potential role in vasospasm: a preliminary observation." Journal of Neurosurgery 97, no. 2 (August 2002): 272–79. http://dx.doi.org/10.3171/jns.2002.97.2.0272.

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Object. The mechanisms leading to vasospasm following subarachnoid hemorrhage (SAH) remain unclear. Accumulation in cerebrospinal fluid (CSF) of free fatty acids (FFAs) may play a role in the development of vasospasm; however, in no previous study have concentrations of FFAs in CSF been examined after SAH. Methods. We collected samples of CSF from 20 patients with SAH (18 cases of aneurysmal SAH and two cases of spontaneous cryptogenic SAH) and used a high-performance liquid chromatography assay to determine the FFA concentrations in these samples. We then compared these findings with FFA concentrations in the CSF of control patients. All FFA concentrations measured 24 hours after SAH were significantly greater than control concentrations (p < 0.01 for palmitic acid and < 0.001 for all other FFAs). All measured FFAs remained elevated for the first 48 hours after SAH (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). After 7 days, a second elevation in all FFAs was observed (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). Samples of CSF collected within 48 hours after SAH from patients in whom angiography and clinical examination confirmed the development of vasospasm after SAH were found to have significantly higher concentrations of arachidonic, linoleic, and palmitic acids than samples collected from patients in whom vasospasm did not develop (p < 0.05). Conclusions. Following SAH, all FFAs are initially elevated. A secondary elevation occurs between 8 and 10 days after SAH. This study provides preliminary evidence of FFA elevation following SAH and of a potential role for FFAs in SAH-induced vasospasm. A prospective study is warranted to determine if CSF concentrations of FFAs are predictive of vasospasm.

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Gormsen, L. C., N. Jessen, J. Gjedsted, S. Gjedde, H. Nørrelund, S. Lund, J. S. Christiansen, S. Nielsen, O. Schmitz, and N. Møller. "Dose-Response Effects of Free Fatty Acids on Glucose and Lipid Metabolism during Somatostatin Blockade of Growth Hormone and Insulin in Humans." Journal of Clinical Endocrinology & Metabolism 92, no. 5 (May 1, 2007): 1834–42. http://dx.doi.org/10.1210/jc.2006-2659.

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Abstract Context: GH and other stress hormones stimulate lipolysis, which may result in free fatty acid (FFA)-mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect. Objective: The objective of the study was to address systematically the dose-response relations between FFAs and insulin sensitivity. Design: We therefore examined eight healthy men for 8 h (6 h basal and 2 h glucose clamp) on four occasions. Intervention: Intralipid was infused at varying rates (0, 3, 6, 12 μl·kg−1·min−1); lipolysis was blocked by acipimox; and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates. Results: This resulted in four different FFA levels between 50 and 2000 μmol/liter, with comparable levels of insulin and counterregulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, nonoxidative glucose disposal, and forearm muscle glucose uptake at FFA levels above 500 μmol/liter. Apart from forearm glucose uptake, the very same parameters were decreased at low FFA levels (∼50 μmol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a maximum at FFA levels approximately 1000 μmol/liter. Conclusion: In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 μmol/liter.

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Kaczmarek, Agata, and Mieczysława Irena Boguś. "The Impact of the Entomopathogenic Fungus Conidiobolus coronatus on the Free Fatty Acid Profile of the Flesh Fly Sarcophaga argyrostoma." Insects 12, no. 11 (October 27, 2021): 970. http://dx.doi.org/10.3390/insects12110970.

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The chemical composition of the insect cuticle varies remarkably between species and their life stages. It can affect host resistance and substrate utilization by invading entomopathogen fungi, such as the soil fungus Conidiobolus coronatus. In this study, Sarcophaga argyrostoma flies were exposed to sporulating C. coronatus colonies for 24 h; the pupae were resistant, but the adults demonstrated 60% mortality. Although the pupae demonstrated no sign of infection nor any abnormal development, our findings indicate that after 24 h of contact with the fungus, the pupae demonstrated a 25.2-fold increase in total cuticular free fatty acids (FFAs) and a 1.9-fold decrease in total internal FFAs. Also, the cuticular FFA increased from 26 to 30, while the internal FFA class increased from 13 to 23. In exposed adults, the total mass of cuticular FFAs increased 1.7-fold, while the number of FFAs stayed the same (32 FFAs). Also, the internal FFA class increased from 26 to 35 and the total FFA mass increased 1.1-fold. These considerable differences between adults and pupae associated with C. coronatus exposure indicate developmental changes in the mechanisms governing lipid metabolism and spatial distribution in the organism, and suggest that cuticular lipids play a vital role in the defence against pathogenic fungi.

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Pilz, Stefan, Hubert Scharnagl, Beate Tiran, Ursula Seelhorst, Britta Wellnitz, Bernhard O. Boehm, Jürgen R. Schaefer, and Winfried März. "Free Fatty Acids Are Independently Associated with All-Cause and Cardiovascular Mortality in Subjects with Coronary Artery Disease." Journal of Clinical Endocrinology & Metabolism 91, no. 7 (July 1, 2006): 2542–47. http://dx.doi.org/10.1210/jc.2006-0195.

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Abstract Context: Free fatty acids (FFAs) are associated with several cardiovascular risk factors and exert harmful effects on the myocardium. Objective: The aim of our study was to elucidate the relationship between FFAs and mortality in subjects who underwent coronary angiography. Design, Setting, and Participants: Ludwigshafen Risk and Cardiovascular Health is a prospective cohort study of Caucasians who had undergone coronary angiography at baseline (1997–2000). During a median time of follow-up of 5.38 yr, 513 deaths had occurred among 3315 study participants with measured FFAs. Main Outcome Measure: Hazard ratios for mortality according to FFA levels were measured. Results: At the fourth quartile of FFAs, fully adjusted hazard ratios for death from any cause and cardiovascular causes were 1.58 (P = 0.002) and 1.83 (P = 0.001), respectively. In persons with angiographic coronary artery disease (CAD), stable CAD, and unstable CAD, the predictive value of FFAs was similar to that in the entire cohort, but the association did not attain statistical significance in persons without CAD analyzed separately. FFA levels were not related to the presence of angiographic CAD but were elevated in subjects with unstable CAD, compared with probands with stable CAD. Furthermore, FFAs increased with the severity of heart failure and were positively correlated with N-terminal pro-B-type natriuretic peptide (P < 0.001). Conclusions: FFA levels independently predict all-cause and cardiovascular mortality in subjects with angiographic CAD. A possible diagnostic use of FFAs warrants further studies, but our results may underline the importance of therapeutic approaches to influence FFA metabolism.

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Kojima, Kouji, Ui Matsumoto, Sumie Keta, Kenji Nakahigashi, Kazutaka Ikeda, Nobuyuki Takatani, Tatsuo Omata, and Makiko Aichi. "High-Light-Induced Stress Activates Lipid Deacylation at the Sn-2 Position in the Cyanobacterium Synechocystis Sp. PCC 6803." Plant and Cell Physiology 63, no. 1 (October 8, 2021): 82–91. http://dx.doi.org/10.1093/pcp/pcab147.

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Abstract Cyanobacterial mutants defective in acyl-acyl carrier protein synthetase (Aas) produce free fatty acids (FFAs) because the FFAs generated by deacylation of membrane lipids cannot be recycled. An engineered Aas-deficient mutant of Synechocystis sp. PCC 6803 grew normally under low-light (LL) conditions (50 µmol photons m−2 s−1) but was unable to sustain growth under high-light (HL) conditions (400 µmol photons m−2 s−1), revealing a crucial role of Aas in survival under the HL conditions. Several-times larger amounts of FFAs were produced by HL-exposed cultures than LL-grown cultures. Palmitic acid accounted for ∼85% of total FFAs in HL-exposed cultures, while C18 fatty acids (FAs) constituted ∼80% of the FFAs in LL-grown cultures. Since C16 FAs are esterified to the sn-2 position of lipids in the Synechocystis species, it was deduced that HL irradiation activated deacylation of lipids at the sn-2 position. Heterologous expression of FarB, the FFA exporter protein of Neisseria lactamica, prevented intracellular FFA accumulation and rescued the growth defect of the mutant under HL, indicating that intracellular FFA was the cause of growth inhibition. FarB expression also decreased the ‘per-cell’ yield of FFA under HL by 90% and decreased the proportion of palmitic acid to ∼15% of total FFA. These results indicated that the HL-induced lipid deacylation is triggered not by strong light per se but by HL-induced damage to the cells. It was deduced that there is a positive feedback loop between HL-induced damage and lipid deacylation, which is lethal unless FFA accumulation is prevented by Aas.

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Jensen, Michael D., Sylvain Cardin, Dale Edgerton, and Alan Cherrington. "Splanchnic free fatty acid kinetics." American Journal of Physiology-Endocrinology and Metabolism 284, no. 6 (June 1, 2003): E1140—E1148. http://dx.doi.org/10.1152/ajpendo.00268.2002.

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These studies were conducted to assess the relationship between visceral adipose tissue free fatty acid (FFA) release and splanchnic FFA release. Steady-state splanchnic bed palmitate ([9,10-3H]palmitate) kinetics were determined from 14 sampling intervals from eight dogs with chronic indwelling arterial, portal vein, and hepatic vein catheters. We tested a model designed to predict the proportion of FFAs delivered to the liver from visceral fat by use of hepatic vein data. The model predicted that 15 ± 2% of hepatic palmitate delivery originated from visceral lipolysis, which was greater ( P = 0.004) than the 11 ± 2% actually observed. There was a good relationship ( r 2 = 0.63) between the predicted and observed hepatic palmitate delivery values, but the model overestimated visceral FFA release more at lower than at higher palmitate concentrations. The discrepancy could be due to differential uptake of FFAs arriving from the arterial vs. the portal vein or to release of FFAs in the hepatic circulatory bed. Splanchnic FFA release measured using hepatic vein samples was strongly related to visceral adipose tissue FFA release into the portal vein. This finding suggests that splanchnic FFA release is a good indicator of visceral adipose tissue lipolysis.

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Prihandoko, Rudi, Davinder Kaur, Coen H. Wiegman, Elisa Alvarez-Curto, Chantal Donovan, Latifa Chachi, Trond Ulven, et al. "Pathophysiological regulation of lung function by the free fatty acid receptor FFA4." Science Translational Medicine 12, no. 557 (August 19, 2020): eaaw9009. http://dx.doi.org/10.1126/scitranslmed.aaw9009.

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Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

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I. S. Sobczak, Amélie, Claudia A. Blindauer, and Alan J. Stewart. "Changes in Plasma Free Fatty Acids Associated with Type-2 Diabetes." Nutrients 11, no. 9 (August 28, 2019): 2022. http://dx.doi.org/10.3390/nu11092022.

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Type 2 diabetes mellitus (T2DM) is associated with increased total plasma free fatty acid (FFA) concentrations and an elevated risk of cardiovascular disease. The exact mechanisms by which the plasma FFA profile of subjects with T2DM changes is unclear, but it is thought that dietary fats and changes to lipid metabolism are likely to contribute. Therefore, establishing the changes in concentrations of specific FFAs in an individual’s plasma is important. Each type of FFA has different effects on physiological processes, including the regulation of lipolysis and lipogenesis in adipose tissue, inflammation, endocrine signalling and the composition and properties of cellular membranes. Alterations in such processes due to altered plasma FFA concentrations/profiles can potentially result in the development of insulin resistance and coagulatory defects. Finally, fibrates and statins, lipid-regulating drugs prescribed to subjects with T2DM, are also thought to exert part of their beneficial effects by impacting on plasma FFA concentrations. Thus, it is also interesting to consider their effects on the concentration of FFAs in plasma. Collectively, we review how FFAs are altered in T2DM and explore the likely downstream physiological and pathological implications of such changes.

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Sørensen, Karina V., Mads H. Kaspersen, Jeppe H. Ekberg, Annette Bauer-Brandl, Trond Ulven, and Kurt Højlund. "Effects of Delayed-Release Olive Oil and Hydrolyzed Pine Nut Oil on Glucose Tolerance, Incretin Secretion and Appetite in Humans." Nutrients 13, no. 10 (September 27, 2021): 3407. http://dx.doi.org/10.3390/nu13103407.

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Background: To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4. Methods: Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At −30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done. Results: PNO-FFA augmented GLP-1 secretion from 0–360 min compared to no oil and PNO-OO (p < 0.01). GIP secretion was increased from 240–360 min after both PNO-FFA and PNO-OO versus no oil (p < 0.01). Both oil treatments suppressed subjective appetite by reducing hunger and prospective food consumption and increasing satiety (p < 0.05). Conclusions: In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

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Bollheimer, LC, DM Kemptner, SM Kagerbauer, TM Kestler, CE Wrede, and R. Buettner. "Intracellular depletion of insulin: a comparative study with palmitate, oleate and elaidate in INS-1 cells." European Journal of Endocrinology 148, no. 4 (April 1, 2003): 481–86. http://dx.doi.org/10.1530/eje.0.1480481.

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OBJECTIVE: Free fatty acids (FFAs) deplete the intracellular insulin stores of pancreatic beta-cells. It has been suggested that this results from a lipotoxic dysregulation of both insulin secretion and insulin synthesis. In the present study, this hypothesis was tested within a 12-h time-course by directly relating the FFA-induced loss of intracellular insulin to corresponding parameters of insulin secretion and de novo biosynthesis. Palmitate, cis-monoenic oleate and the trans-monoenic elaidate were employed as model FFAs to elucidate potentially different effects due to chain length and configuration. METHODS: INS-1 cells were incubated for 1, 4 or 12 h with 11.2 mmol/l glucose with 200 micromol/l palmitate, oleate or elaidate and compared with non-FFA-exposed controls with respect to content and secretion of immunoreactive insulin (IRI). Biosynthesis of insulin was monitored by pulse-labeling experiments and by Northern blot analysis. RESULTS: IRI content dropped by 50-60% after a short-term exposure with all FFAs employed (P< or =0.001). It tended to recover after 12 h of treatment with oleate and elaidate but not with palmitate. FFA treatment increased insulin secretion by 25% (P< or =0.05) which could not account quantitatively for the intracellular loss. FFA-induced changes in insulin biosynthesis did not correlate clearly with the FFA-induced intracellular loss. CONCLUSIONS: The FFA-induced loss of IRI is an acute effect independent of the FFA employed. It cannot be sufficiently explained by FFA-induced perturbances of IRI secretion and biosynthesis. We therefore postulate an additional FFA-triggered mechanism, e.g. intracellular IRI degradation.

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Xu, Fangfang, Han Zhou, Xiumei Liu, Xiuli Zhang, Zhiwei Wang, Tao Hou, Jixia Wang, et al. "Label-free cell phenotypic study of FFA4 and FFA1 and discovery of novel agonists of FFA4 from natural products." RSC Advances 9, no. 26 (2019): 15073–83. http://dx.doi.org/10.1039/c9ra02142f.

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Seo, Woo-Keun, Juyeon Kim, Yoo Hwan Kim, Ji Hyun Kim, Kyungmi Oh, Seong-Beom Koh, and Hong Seok Seo. "Elevated Free Fatty Acid is Associated with Cardioembolic Stroke Subtype." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 38, no. 6 (November 2011): 874–79. http://dx.doi.org/10.1017/s0317167100012464.

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Background and Objectives:Free fatty acids (FFAs), an important energy substrate, have an association with cardiovascular diseases, such as atherosclerosis, myocardial dysfunction and abnormal cardiac rhythm. However, limited reports are available on the association between FFAs and ischemic stroke. We hypothesized that plasma FFA concentration could be associated with an ischemic stroke, emphasizing the relationship between FFA and subtypes of ischemic stroke.Methods:A cross-sectional study examined the association between FFA concentration and subtypes of stroke and cerebral atherosclerosis from a hospital-based acute stroke registry.Results:Data of 715 stroke patients were analyzed. The concentration of FFA was highest in the cardioembolic stroke subtype compared with the other stroke subtypes. Logistic regression analysis revealed that an increase in FFA concentration was significantly associated with the cardioembolic subtype after the adjustment of covariates. FFA concentration was also higher in patients with atrial fibrillation (AF) than those without AF. According to the presence of atherosclerotic stenosis, no significantly difference of FFA concentration was found for intracranial and extracranial cerebral arterial atherosclerosis.Conclusion:Here we report a significant association between fasting FFA concentration and the cardioembolic stroke subtype. AF is suggested as the mediating factor between FFA and the cardioembolic stroke subtype.

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Wang, Yu, Hui-Wen Zhang, Yuan-Lin Guo, Cheng-Gang Zhu, Na-Qiong Wu, and Jian-Jun Li. "Free fatty acids as a marker for predicting periprocedural myocardial injury after coronary intervention." Postgraduate Medical Journal 95, no. 1119 (January 2019): 18–22. http://dx.doi.org/10.1136/postgradmedj-2018-136137.

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BackgroundPrevious studies have revealed that plasma levels of free fatty acids (FFAs) are related to cardiovascular risk. However, whether FFAs could predict periprocedural myocardial injury (PMI) following percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) remains unclear.PurposeThis study aimed to investigate the relationship of FFAs to PMI in untreated patients with CAD who underwent PCI.MethodsA total of 374 consecutive patients with CAD without lipid-lowering treatment on admission and with normal preprocedural cardiac troponin I (cTnI) levels who underwent PCI were prospectively enrolled. The baseline characteristics were collected and PMI was evaluated by cTnI analysis within 24 hours. The relation of preprocedural FFA levels to peak cTnI values after PCI was examined.ResultsPreprocedural FFAs were positively correlated with peak cTnI values after PCI in both simple regression model (β=0.119, p=0.021) and multiple regression model (β=0.198, p=0.001). Patients with higher FFA levels had higher postprocedural cTnI levels compared with those with normal FFA levels (0.27±0.68 ng/mL vs 0.66±0.31 ng/mL, p=0.014). In the multivariable model, preprocedural FFA levels were associated with an increased risk of postprocedural cTnI elevation above 1× upper limit of normal (ULN, OR: 1.185, 95% CI 0.997 to 1.223, p=0.019) up to 10× ULN (OR: 1.132, 95% CI 1.005 to 1.192, p=0.003) .ConclusionsThe present study first suggested that elevated FFA levels were associated with an increased risk of PMI in untreated patients with CAD. Further study with large sample size may be needed to confirm our findings.

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Xue, Yun, Ting Guo, Lifang Zou, Yingxin Gong, Bing Wu, Zhihua Yi, Tianyu Jia, et al. "Evodiamine Attenuates P2X7-Mediated Inflammatory Injury of Human Umbilical Vein Endothelial Cells Exposed to High Free Fatty Acids." Oxidative Medicine and Cellular Longevity 2018 (August 19, 2018): 1–10. http://dx.doi.org/10.1155/2018/5082817.

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Insulin resistance and type 2 diabetes mellitus (T2DM) are highly prevalent around the world. Elevated concentrations of free fatty acids (FFAs) are closely related to insulin resistance and T2DM. P2X7 receptor is an ion channel gated by ATP, which is implicated in various scenarios including immune response, pain, and inflammation. In this study, we have explored whether P2X7 receptor is involved in pathological changes in human umbilical vein endothelial cells (HUVECs) induced by high FFA treatment, and the potential beneficial effects of evodiamine. Evodiamine could effectively suppress the enhanced expression of P2X7 receptor caused by high FFAs at both mRNA and protein levels. In addition, high FFA-induced cytotoxicity, the upregulated release of ATP, and production of reactive oxygen species (ROS) could be ameliorated by evodiamine in HUVECs. Evodiamine could also reverse the decreased NO formation and the increased adhesive events of immune cells at high FFAs. Moreover, evodiamine inhibited P2X7-dependent TNF-α expression and ERK 1/2 phosphorylation due to high FFAs. All these results indicated that evodiamine could correct the upregulated expression of P2X7 receptor induced under high FFA condition in HUVECs, and consequently suppressed oxidative stress and inflammatory responses.

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Hanuš, O., J. Vegricht, J. Frelich, A. Macek, M. Bjelka, F. Louda, and L. Janů. "Analysis of raw cow milk quality according to free fatty acid contents in the Czech Republic." Czech Journal of Animal Science 53, No. 1 (January 14, 2008): 17–30. http://dx.doi.org/10.17221/2717-cjas.

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The concentration (c) of free fatty acids (FFAs) in milk is an indicator of dairy cow nutrition, milk straining, its bacterial contamination and storage quality. High FFA concentrations (cs) caused by lipolysis can damage the quality properties of milk products. Therefore the FFA content is introduced thanks to an increase in the efficiency of modern analytical methods as a milk quality indicator and as an indicator for its price as well. The goal of this paper was to analyse the FFA relations to the other milk quality indicators. The data set (n = 11 586) was evaluated by regression methods. In November and December the respective FFA means were 0.614 ± 0.458 and 0.835 ± 0.491 mmol/100 g with a relatively high variability of 74.6 and 58.8%. The frequency of unsatisfactory FFA values (> 1.3) was 7.51 and 13.93%. Casein content (r = –0.17; P < 0.01) and crude protein content (r = –0.12; P < 0.01) were related more closely with FFA c. The FFAs can increase by 0.066 mmol/100 g with casein decrease by 0.10%. The FFAs in milk fat can slightly increase by the supply of energy to dairy cows (protein and casein decrease) and rise with the deteriorating health state of mammary gland (lactose, r = –0.14; P < 0.01) as well. The somatic cell count correlated with FFAs more weakly (r = 0.07; P < 0.05), similarly like the total mesophilic bacteria count (r = 0.11; P < 0.01), relatively more closely the psychrotrophic bacteria count (r = 0.27; P < 0.05). The deterioration of almost all hygienic indicators signified an FFA c increase. The urea content correlated with FFAs weakly (r = –0.08; P < 0.05) and the fat content imperceptibly as a component of similar substance like FFAs. The mechanical milk stress led to FFA liberation from fat esters proportionally to the intervention intensity (P < 0.001). Even a relatively small mechanical stress caused by mixing comparable to the current milking technology, milk transport and storage increased the FFA c of milk fat from 1.11 ± 0.19 to 1.80 ± 0.40 mmol/100 g (P < 0.05). The highest experimental stress up to 6.88 ± 0.55 mmol/100 g (P < 0.001).

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Journal articles on the topic 'FFA3'

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