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Author: Grafiati

Published: 10 December 2022

Last updated: 28 January 2023

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1

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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2

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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3

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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4

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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5

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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6

Nnyamah, Christine, Barton Wicksteed, and Brian Layden. "PSUN82 The Gut Microbiome Regulates Healthy Adipose Tissue Expansion via the Action of FFA2." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A25. http://dx.doi.org/10.1210/jendso/bvac150.053.

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Abstract The obesity pandemic is a major health concern driving Type 2 Diabetes (T2D) and cardiovascular disease (CVD). One novel pathogenetic factor of obesity is the gut microbiome (GM), that is the microbes that reside in the digestive tract. Changes in the GM have profound effects on the obesity. These symbiotic microbes break down dietary fiber that are otherwise indigestible, releasing nutrients (in particular, short chain fatty acids, SCFAs). Free Fatty Acid Receptor 2 (FFA2) is a G-protein coupled receptor (GPCR) that senses SCFAs and influences secretion of the appetite-regulating proteins GLP-1 and PYY from enteroendocrine cells. However, its role in adipose tissue is less clear. While highly expressed in adipose tissue, research using global knockouts (KOs) of FFA2 in mouse models has observed conflicting phenotypic results. Here, we use adipocytes isolated from FFA2-KO and WT mice and SCFA-supplemented media to demonstrate that acetate, a primary ligand of FFA2, leads to increased adipogenesis. This expansion of total adipocyte population rather than individual size has been shown to greatly decrease metabolic health complications in highly obese individuals. Our ongoing research aims to explore the in vitro effects of FFA2 on lipogenesis, lipolysis, and secretion of adipokines. Primarily, we are exploring these outcomes in vivo using novel adipose-specific FFA2 KO (AdFFA2-KO) mice which we show have no congenital defects and are metabolically similar to FFA2 floxxed control mice on a normal chow diet. Our ongoing research challenges the mice with obesogenic diets to observe the effects of metabolic strain on FFA2 function specifically in adipose tissue. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

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7

Zhang, J., S. Cheng, Y. Wang, X. Yu, and J. Li. "Identification and characterization of the free fatty acid receptor 2 (FFA2) and a novel functional FFA2-like receptor (FFA2L) for short-chain fatty acids in pigs: Evidence for the existence of a duplicated FFA2 gene (FFA2L) in some mammalian species." Domestic Animal Endocrinology 47 (April 2014): 108–18. http://dx.doi.org/10.1016/j.domaniend.2013.10.004.

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8

Fuller, Miles, Medha Priyadarshini, Sean M. Gibbons, Anthony R. Angueira, Michael Brodsky, M. Geoffrey Hayes, Petia Kovatcheva-Datchary, et al. "The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis." American Journal of Physiology-Endocrinology and Metabolism 309, no. 10 (November 15, 2015): E840—E851. http://dx.doi.org/10.1152/ajpendo.00171.2015.

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The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene ( Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2−/− mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2−/− and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2−/− mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.

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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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10

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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12

Bindels, Laure B., Evelyne M. Dewulf, and Nathalie M. Delzenne. "GPR43/FFA2: physiopathological relevance and therapeutic prospects." Trends in Pharmacological Sciences 34, no. 4 (April 2013): 226–32. http://dx.doi.org/10.1016/j.tips.2013.02.002.

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13

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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14

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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15

Sleeth, Michelle L., Emily L. Thompson, Heather E. Ford, Sagen E. K. Zac-Varghese, and Gary Frost. "Free fatty acid receptor 2 and nutrient sensing: a proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation." Nutrition Research Reviews 23, no. 1 (May 19, 2010): 135–45. http://dx.doi.org/10.1017/s0954422410000089.

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The way in which the composition of the diet may affect appetite, food intake and body weight is now receiving considerable attention in a bid to halt the global year-on-year rise in obesity prevalence. Epidemiological evidence suggests that populations who follow a fibre-rich, traditional diet are likely to have a lower body weight and improved metabolic parameters than their Western-diet counterparts. The colonic effects of fibre, and more specifically the SCFA that the fermentation process produces, may play a role in maintaining energy homeostasis via their action on the G-coupled protein receptor free fatty acid receptor 2 (FFA2; formerly GPR43). In the present review, we summarise the evidence for and against the role of FFA2 in energy homeostasis circuits and the possible ways that these could be exploited therapeutically. We also propose that the decline in fibre content of the diet since the Industrial Revolution, particularly fermentable fractions, may have resulted in the FFA2-mediated circuits being under-utilised and hence play a role in the current obesity epidemic.

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Swaminath, Gayathri, Peter Jaeckel, Qi Guo, Mario Cardozo, Jennifer Weiszmann, Richard Lindberg, Yingcai Wang, Ralf Schwandner, and Yang Li. "Mutational analysis of G-protein coupled receptor – FFA2." Biochemical and Biophysical Research Communications 405, no. 1 (February 2011): 122–27. http://dx.doi.org/10.1016/j.bbrc.2010.12.139.

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Brown, Andrew J., Christina Tsoulou, Emma Ward, Elaine Gower, Nisha Bhudia, Forhad Chowdhury, Tony W. Dean, Nicolas Faucher, Akanksha Gangar, and Simon J. Dowell. "Pharmacological properties of acid N -thiazolylamide FFA2 agonists." Pharmacology Research & Perspectives 3, no. 3 (May 8, 2015): e00141. http://dx.doi.org/10.1002/prp2.141.

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Akiba, Yasutada, Koji Maruta, Kazuyuki Narimatsu, Hyder Said, Izumi Kaji, Ayaka Kuri, Ken-ichi Iwamoto, Atsukazu Kuwahara, and Jonathan D. Kaunitz. "FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 313, no. 2 (August 1, 2017): G117—G128. http://dx.doi.org/10.1152/ajpgi.00041.2017.

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Serotonin (5-HT), predominantly synthesized and released by enterochromaffin cells, is implicated in gastrointestinal symptoms such as emesis, abdominal pain, and diarrhea. Because luminal short-chain fatty acids (SCFAs) release 5-HT from enterochromaffin cells, which express the SCFA receptor free fatty acid receptor 2 (FFA2) in rat duodenum, we examined the effects of the selective FFA2 agonist phenylacetamide-1 (PA1) on duodenal 5-HT release with consequent bicarbonate secretion [duodenal bicarbonate secretion (DBS)] and on indomethacin (IND)-induced enteropathy. Intestinal injury was induced by IND (10 mg/kg sc) with or without PA1. We measured DBS in vivo in a duodenal loop perfused with PA1 while measuring 5-HT released in the portal vein. Duodenal blood flow was measured by laser-Doppler flowmetry. IND induced small intestinal ulcers with duodenal sparing. PA1 given with IND (IND + PA1) dose dependently induced duodenal erosions. IND + PA1-induced duodenal lesions were inhibited by the FFA2 antagonist GLPG-0974, ondansetron, or omeprazole but not by RS-23597 or atropine. Luminal perfusion of PA1 augmented DBS accompanied by increased portal blood 5-HT concentrations with approximately eight times more release at 0.1 mM than at 1 µM, with the effects inhibited by coperfusion of GLPG-0974. Luminal PA1 at 1 µM increased, but at 0.1 mM diminished, duodenal blood flow. Cosuperfusion of PA1 (0.1 mM) decreased acid-induced hyperemia, further reduced by IND pretreatment but restored by ondansetron. These results suggest that, although FFA2 activation enhances duodenal mucosal defenses, FFA2 overactivation during ulcerogenic cyclooxygenase inhibition may increase the vulnerability of the duodenal mucosa to gastric acid via excessive 5-HT release and 5-HT3receptor activation, implicated in foregut-related symptoms such as emesis and epigastralgia.NEW & NOTEWORTHY Luminal free fatty acid receptor 2 agonists stimulate enterochromaffin cells and release serotonin, which enhances mucosal defenses in rat duodenum. However, overdriving serotonin release with high luminal concentrations of free fatty acid 2 ligands such as short-chain fatty acids injures the mucosa by decreasing mucosal blood flow. These results are likely implicated in serotonin-related dyspeptic symptom generation because of small intestinal bacterial overgrowth, which is hypothesized to generate excess SCFAs in the foregut, overdriving serotonin release from enterochromaffin cells.

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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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Kang, Jisoo, and Dong-Soon Im. "FFA2 Activation Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice." Biomolecules & Therapeutics 28, no. 3 (May 1, 2020): 267–71. http://dx.doi.org/10.4062/biomolther.2019.160.

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Fuller, Miles, Xiaoran Li, Robert Fisch, Moneb Bughara, Barton Wicksteed, Petia Kovatcheva-Datchary, and Brian T. Layden. "FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics." PLOS ONE 11, no. 12 (December 13, 2016): e0167837. http://dx.doi.org/10.1371/journal.pone.0167837.

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Vanhoutte, F., F. Namour, S. Dupont, W. Haazen, M. Petkova, A. Van der Aa, G. van ‘t Klooster, and J. Beetens. "DOP070 The FFA2 antagonist GLPG0974: opportunity to treat neutrophil-driven inflammation." Journal of Crohn's and Colitis 8 (February 2014): S48. http://dx.doi.org/10.1016/s1873-9946(14)60095-7.

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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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Liu, Jun-Li, Irina Segovia, Xiao-Lin Yuan, and Zu-hua Gao. "Controversial Roles of Gut Microbiota-Derived Short-Chain Fatty Acids (SCFAs) on Pancreatic β-Cell Growth and Insulin Secretion." International Journal of Molecular Sciences 21, no. 3 (January 30, 2020): 910. http://dx.doi.org/10.3390/ijms21030910.

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In the past 15 years, gut microbiota emerged as a crucial player in health and disease. Enormous progress was made in the analysis of its composition, even in the discovery of novel species. It is time to go beyond mere microbiota-disease associations and, instead, provide more causal analyses. A key mechanism of metabolic regulation by the gut microbiota is through the production of short-chain fatty acids (SCFAs). Acting as supplemental nutrients and specific ligands of two G-protein-coupled receptors (GPCRs), they target the intestines, brain, liver, and adipose tissue, and they regulate appetite, energy expenditure, adiposity, and glucose production. With accumulating but sometimes conflicting research results, key questions emerged. Do SCFAs regulate pancreatic islets directly? What is the effect of β-cell-specific receptor deletions? What are the mechanisms used by SCFAs to regulate β-cell proliferation, survival, and secretion? The receptors FFA2/3 are normally expressed on pancreatic β-cells. Deficiency in FFA2 may have caused glucose intolerance and β-cell deficiency in mice. However, this was contrasted by a double-receptor knockout. Even more controversial are the effects of SCFAs on insulin secretion; there might be no direct effect at all. Unable to draw clear conclusions, this review reveals some of the recent controversies.

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Vanhoutte, Frédéric P., Florence S. Namour, Sonia Dupont, Mathieu Pizzonero, Steve De Vos, Laurent Sanière, Annegret van der Aa, Johan Beetens, and Gerben van 't Klooster. "Mo1234 The FFA2 Antagonist GLPG0974: A Promising Approach to Treat Neutrophil-Driven Inflammation." Gastroenterology 146, no. 5 (May 2014): S—593. http://dx.doi.org/10.1016/s0016-5085(14)62149-1.

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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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Lee, Taeweon, Ralf Schwandner, Gayathri Swaminath, Jennifer Weiszmann, Mario Cardozo, Joanne Greenberg, Peter Jaeckel, et al. "Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2." Molecular Pharmacology 74, no. 6 (September 25, 2008): 1599–609. http://dx.doi.org/10.1124/mol.108.049536.

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Wang, Yingcai, Xianyun Jiao, Frank Kayser, Jiwen Liu, Zhongyu Wang, Malgorzata Wanska, Joanne Greenberg, et al. "The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators." Bioorganic & Medicinal Chemistry Letters 20, no. 2 (January 2010): 493–98. http://dx.doi.org/10.1016/j.bmcl.2009.11.112.

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31

Ma, Liang, Taijin Wang, Min Shi, Ping Fu, Heying Pei, and Haoyu Ye. "Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists." Chemical Biology & Drug Design 88, no. 1 (February 15, 2016): 26–37. http://dx.doi.org/10.1111/cbdd.12729.

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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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Agapay, R. C., A. W. Go, and Y. H. Ju. "Synthesis of symmetrical structured triglycerides via a bottom-up process." IOP Conference Series: Materials Science and Engineering 1195, no. 1 (October 1, 2021): 012017. http://dx.doi.org/10.1088/1757-899x/1195/1/012017.

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Abstract The synthesis of symmetrical structured triglycerides (STG) through a bottom-up approach was previously shown to produce 1,3-dioleoyl-2-palmitoyl glycerol in significant quantities. This solvent-free lipase-catalyzed process, consisting of a low-temperature (40 °C) esterification step with glycerol dosing followed by a high-temperature (60 °C) esterification step, was further investigated in the production of symmetrical medium-and-long-chain triglycerides (MLCT). By replacing oleic acid with capric acid in the first step or the palmitic acid by either capric acid or lauric acid in the second step, the effects of free fatty chain length and sequence of fatty acid addition on STG production were established. These produced 1,3-dicaproyl-2-oleoyl glycerol, 1,3-dioleoyl-2-caproyl glycerol, and 1,3-dioleoyl-2-lauroyl glycerol at concentrations of 36.98 g, 36.77 g, and 37.08 g per 100 g of triglycerides respectively after 72 h at an overall FFA1:FFA2:Glycerol of 2:1:1 and 4 g Novozyme 435 per 100 g reactants, without the purification of intermediates and products. The sequence of fatty acid addition had the most significant effect as purer STG products can be obtained when the medium chain fatty acid is introduced in the first step. As the process was carried out without solvents, the STG produced are appropriate for functional food or nutraceutical applications.

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Akiba, Yasutada, and Jonathan D. Kaunitz. "Su240 ENHANCED FFA2/5-HT MEDIATED ANION SECRETION IN MOUSE DUODENUM – A MODEL OF FUNCTIONAL DYSPEPSIA?" Gastroenterology 160, no. 6 (May 2021): S—650. http://dx.doi.org/10.1016/s0016-5085(21)02265-4.

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36

Namour, Florence, René Galien, Tim Van Kaem, Annegret Van der Aa, Frédéric Vanhoutte, Johan Beetens, and Gerben Klooster. "Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects." British Journal of Clinical Pharmacology 82, no. 1 (May 2016): 139–48. http://dx.doi.org/10.1111/bcp.12900.

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37

Hansen, Anders Højgaard, Eugenia Sergeev, Sunil K. Pandey, Brian D. Hudson, Elisabeth Christiansen, Graeme Milligan, and Trond Ulven. "Development and Characterization of a Fluorescent Tracer for the Free Fatty Acid Receptor 2 (FFA2/GPR43)." Journal of Medicinal Chemistry 60, no. 13 (June 16, 2017): 5638–45. http://dx.doi.org/10.1021/acs.jmedchem.7b00338.

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38

Maruta, Koji, Yasutada Akiba, Izumi Kaji, and Jonathan D. Kaunitz. "Serotonin Released by FFA2 Activation Stimulates HCO 3 - Secretion, but Induces Mucosal Injury in Rat Duodenum." Gastroenterology 152, no. 5 (April 2017): S13—S14. http://dx.doi.org/10.1016/s0016-5085(17)30420-1.

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39

Said, Hyder, Yasutada Akiba, Izumi Kaji, Kazuyuki Narimatsu, and Jonathan D. Kaunitz. "Sa1725 FFA2 Activation Suppresses Basal and Stimulated Gastric Acid Secretion via 5-HT3 Receptor Activation in Rats." Gastroenterology 148, no. 4 (April 2015): S—315. http://dx.doi.org/10.1016/s0016-5085(15)31041-6.

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Akiba, Yasutada, Takeshi Takajo, and Jonathan D. Kaunitz. "Mo1171 - Functional Localization of Ffa2 to the Basolateral Membrane of Enterochromaffin Cells in Rat and Mouse Duodenum." Gastroenterology 154, no. 6 (May 2018): S—695. http://dx.doi.org/10.1016/s0016-5085(18)32452-1.

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Hudson, Brian D., Maria E. Due-Hansen, Elisabeth Christiansen, Anna Mette Hansen, Amanda E. Mackenzie, Hannah Murdoch, Sunil K. Pandey, et al. "Defining the Molecular Basis for the First Potent and Selective Orthosteric Agonists of the FFA2 Free Fatty Acid Receptor." Journal of Biological Chemistry 288, no. 24 (April 15, 2013): 17296–312. http://dx.doi.org/10.1074/jbc.m113.455337.

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42

Tang, Gang, Yi Du, Haochen Guan, Jieshuang Jia, Nan Zhu, Yuping Shi, Shu Rong, and Weijie Yuan. "Butyrate ameliorates skeletal muscle atrophy in diabetic nephropathy by enhancing gut barrier function and FFA2‐mediated PI3K/Akt/mTOR signals." British Journal of Pharmacology 179, no. 1 (November 23, 2021): 159–78. http://dx.doi.org/10.1111/bph.15693.

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43

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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Pizzonero, Mathieu, Sonia Dupont, Marielle Babel, Stéphane Beaumont, Natacha Bienvenu, Roland Blanqué, Laëtitia Cherel, et al. "Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic." Journal of Medicinal Chemistry 57, no. 23 (December 2014): 10044–57. http://dx.doi.org/10.1021/jm5012885.

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Kaji, Izumi, Shin-ichiro Karaki, Ryo Tanaka, and Atsukazu Kuwahara. "M1718 Fructo-Oligosaccharide (FOS) Supplementation Increases Enteroendocrine L Cells Containing GLP-1 and SCFA Receptor GPR43 (Ffa2) in the Large Intestine." Gastroenterology 138, no. 5 (May 2010): S—405. http://dx.doi.org/10.1016/s0016-5085(10)61861-6.

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46

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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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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