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https://www.readbyqxmd.com/read/28183801/fatty-acid-16-4-n-3-stimulates-a-gpr120-induced-signaling-cascade-in-splenic-macrophages-to-promote-chemotherapy-resistance
#1
Julia M Houthuijzen, Ilse Oosterom, Brian D Hudson, Akira Hirasawa, Laura G M Daenen, Chelsea M McLean, Steffen V F Hansen, Marijn T M van Jaarsveld, Daniel S Peeper, Sahar Jafari Sadatmand, Jeanine M L Roodhart, Chris H A van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile E Voest
Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid, 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid), induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80(+)/CD11b(low) macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80(+)/CD11b(low) macrophages as the relevant receptor for 16:4(n-3)...
February 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28169160/corrigendum-to-discovery-of-benzofuran-propanoic-acid-gpr120-agonists-from-uhts-hit-to-mechanism-based-pharmacodynamic-effects-bioorg-med-chem-lett-26-2016-5724-5728
#2
Matthew Lombardo, Kate Bender, Clare London, Michael A Plotkin, Melissa Kirkland, Joel Mane, Michele Pachanski, Wayne Geissler, John Cummings, Bahanu Habulihaz, Taro E Akiyama, Jerry Di Salvo, Maria Madeira, Joanna Pols, Mary Ann Powles, Michael F Finley, Eric Johnson, Thomas Roussel, Victor N Uebele, Alejandro Crespo, Dennis Leung, Candice Alleyne, Dorina Trusca, Ying Lei, Andrew D Howard, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
No abstract text is available yet for this article.
February 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28159555/different-effects-of-g-protein-coupled-receptor-120-gpr120-and-gpr40-on-cell-motile-activity-of-highly-migratory-osteosarcoma-cells
#3
Kaede Takahashi, Kaori Fukushima, Yuka Onishi, Yusuke Node, Karin Inui, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
G-protein-coupled receptor 120 (GPR120) and GPR40 are members of free fatty acid (FFA) receptors and mediate a variety of biological responses through binding of medium- and long-chain FFAs. Recently, it has been reported that GPR120 and GPR40 regulated cellular functions of cancer cells. In the present study, to assess whether GPR120 and GPR40 are involved in the enhancement of cell motile activity of osteosarcoma cells, we established highly migratory (MG63-R7) cells from osteosarcoma MG-63 cells. The expression level of GPR120 gene was significantly higher in MG63-R7 cells than in MG-63 cells, while no change of GPR40 expression was observed...
January 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28148462/exploration-of-phenylpropanoic-acids-as-agonists-of-the-free-fatty-acid-receptor-4-ffa4-identification-of-an-orally-efficacious-ffa4-agonist
#4
Steven M Sparks, Christopher Aquino, Pierette Banker, Jon L Collins, David Cowan, Caroline Diaz, Steven T Dock, Donald L Hertzog, Xi Liang, Erin D Swiger, Josephine Yuen, Grace Chen, Channa Jayawickreme, David Moncol, Christopher Nystrom, Vincent Rash, Thomas Rimele, Shane Roller, Sean Ross
The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes...
January 17, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105282/discovery-of-chromane-propionic-acid-analogues-as-selective-agonists-of-gpr120-with-in-vivo-activity-in-rodents
#5
Gregory L Adams, Francisco Velazquez, Charles Jayne, Unmesh Shah, Shouwu Miao, Eric R Ashley, Maria Madeira, Taro E Akiyama, Jerry Di Salvo, Takao Suzuki, Nengxue Wang, Quang Truong, Eric Gilbert, Dan Zhou, Andreas Verras, Melissa Kirkland, Michele Pachanski, Maryann Powles, Wu Yin, Feroze Ujjainwalla, Srikanth Venkatraman, Scott D Edmondson
GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105274/design-synthesis-and-evaluation-of-novel-and-selective-g-protein-coupled-receptor-120-gpr120-spirocyclic-agonists
#6
Jason M Cox, Hong D Chu, Mariappan V Chelliah, John S Debenham, Keith Eagen, Ping Lan, Matthew Lombardo, Clare London, Michael A Plotkin, Unmesh Shah, Zhongxiang Sun, Henry M Vaccaro, Srikanth Venkatraman, Takao Suzuki, Nengxue Wang, Eric R Ashley, Alejandro Crespo, Maria Madeira, Dennis H Leung, Candice Alleyne, Aimie M Ogawa, Sarah Souza, Brande Thomas-Fowlkes, Jerry Di Salvo, Adam Weinglass, Melissa Kirkland, Michele Pachanski, Mary Ann Powles, Effie Tozzo, Taro E Akiyama, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28039475/gpr120-a-potential-therapeutic-target-for-experimental-colitis-in-il-10-deficient-mice
#7
Jie Zhao, Honggang Wang, Peiliang Shi, Wenbo Wang, Ye Sun
It has been proved that interleukin-10-knockout (IL-10 KO) mice display the most similar characteristics to that of human Crohn's disease (CD). Docosahexaenoic acid (DHA) has well established beneficial effects on human and animal models health with potent anti-inflammatory effects with poorly understood mechanisms. This study was aimed at figuring out whether DHA could ameliorate the Crohn's colitis by activating GPR120 and whether GPR120 could be a potential therapeutic target for CD.16 week-old mice included in our present study were divided into three groups, WT group, IL-10 KO group and DHA group(IL-10 KO mice with DHA treatment, i...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28025563/novel-structural-approaches-to-study-gpcr-regulation
#8
REVIEW
Marco A Alfonzo-Méndez, Rocío Alcántara-Hernández, J Adolfo García-Sáinz
BACKGROUND: Upon natural agonist or pharmacological stimulation, G protein-coupled receptors (GPCRs) are subjected to posttranslational modifications, such as phosphorylation and ubiquitination. These posttranslational modifications allow protein-protein interactions that turn off and/or switch receptor signaling as well as trigger receptor internalization, recycling or degradation, among other responses. Characterization of these processes is essential to unravel the function and regulation of GPCR...
December 23, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28017961/ginsenoside-rb2-enhances-the-anti-inflammatory-effect-of-%C3%AF-3-fatty-acid-in-lps-stimulated-raw264-7-macrophages-by-upregulating-gpr120-expression
#9
Qi Huang, Ting Wang, He-Yao Wang
Recent studies confirm that chronic low-grade inflammation is closely associated with metabolic syndromes, and anti-inflammatory therapy is a potential approach for treating cardiovascular diseases and type 2 diabetes. Accumulating evidence suggests that GPR120 activation is a feasible solution to ameliorating chronic inflammation and improving glucose metabolism. In this study we investigated whether ginsenoside Rb2 (Rb2), which exhibited regulatory activities in glucose and lipid metabolism, affected GPR120 expression in lipopolysaccharide (LPS)-activated mouse macrophage RAW264...
December 26, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27999451/ffar4-gpr120-signaling-is-not-required-for-anti-inflammatory-and-insulin-sensitizing-effects-of-omega-3-fatty-acids
#10
Simone Isling Pærregaard, Marianne Agerholm, Annette Karen Serup, Tao Ma, Bente Kiens, Lise Madsen, Karsten Kristiansen, Benjamin Anderschou Holbech Jensen
Free fatty acid receptor-4 (FFAR4), also known as GPR120, has been reported to mediate the beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) by inducing an anti-inflammatory immune response. Thus, activation of FFAR4 has been reported to ameliorate chronic low-grade inflammation and insulin resistance accompanying obesity. However, conflicting reports on the role of FFAR4 in mediating the effects of ω3-PUFAs are emerging, suggesting that FFAR4 may not be the sole effector. Hence analyses of the importance of this receptor in relation to other signaling pathways and prominent effects of ω3-PUFAs remain to be elucidated...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/27986832/placental-and-cord-blood-methylation-of-genes-involved-in-energy-homeostasis-association-with-fetal-growth-and-neonatal-body-composition
#11
Marta Díaz, Cristina García, Giorgia Sebastiani, Francis de Zegher, Abel López-Bermejo, Lourdes Ibáñez
Low weight at birth associates with subsequent susceptibility to diabetes. Epigenetic modulation is among the mechanisms potentially mediating this association. We performed a genome-wide DNA methylation analysis in placentas from term infants born appropriate-for-gestational-age (AGA) or small-for-gestational-age (SGA), to identify new genes related to fetal growth and neonatal body composition. Candidate genes were validated by bisulfite pyrosequencing (30 AGA, 21 SGA) and also analyzed in cord blood. Gene expression analyses were performed by RT-PCR...
December 16, 2016: Diabetes
https://www.readbyqxmd.com/read/27980130/insulinotropic-effects-of-gpr120-agonists-are-altered-in-obese-diabetic-and-obese-non-diabetic-states
#12
Dan Zhang, Wing Yan So, Yi Wang, Shang Ying Wu, Qianni Cheng, Po Sing Leung
G-protein-coupled receptor 120 (GPR120) is a putative target for obesity and diabetes therapies. However, it remains controversial whether resident GPR120 plays a direct regulatory role in islet β-cell insulin secretion. The present study examined this issue in isolated rodent islets and rat β-cell line INS-1E, and assessed the role of GPR120 in islet insulin secretion in obese non-diabetic (OND) and diabetic states. GPR120 expression was detected in rodent islet β-cells. Docosahexaenoic acid (DHA) and synthetic GPR120 agonist GSK137647 (GSK) augmented insulin release from rat/mouse islets and INS-1E; DHA effects were partially mediated by GPR40...
February 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/27959384/pro-metastatic-intracellular-signaling-of-the-elaidic-trans-fatty-acid
#13
Kiyomu Fujii, Yi Luo, Rina Fujiwara-Tani, Shingo Kishi, Song He, Shuyun Yang, Takamitsu Sasaki, Hitoshi Ohmori, Hiroki Kuniyasu
Trans fatty acids (TFAs) are risk factors of cardiovascular disorders, and a few studies have reported the cancer-promoting effects of TFAs. In the present study, we examined the effects and signaling of elaidic acid (EA), a TFA, in colorectal cancer (CRC) cells. Oral intake of EA increased the metastasis of CT26 mouse CRC cells by inducing the expression of stemness markers nucleostemin (NS) and CD133. Mechanisms underlying EA-induced signaling were confirmed by determining the binding of EA to G-protein coupled receptor 40 (GPR40) and GPR120 by performing surface protein internalization assay...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27881903/forskolin-inhibits-lipopolysaccharide-induced-modulation-of-mcp-1-and-gpr120-in-3t3-l1-adipocytes-through-an-inhibition-of-nf%C3%AE%C2%BAb
#14
Jeanne Durendale Chiadak, Tatjana Arsenijevic, Kevin Verstrepen, Françoise Gregoire, Nargis Bolaky, Valérie Delforge, Véronique Flamand, Jason Perret, Christine Delporte
In an obese state, Toll-like receptor-4 (TLR-4) upregulates proinflammatory adipokines secretion including monocyte chemotactic protein-1 (MCP-1) in adipose tissue. In contrast, G-protein coupled receptor 120 (GPR120) mediates antiobesity effects. The aim of this study was to determine the signaling pathway by which Forskolin (FK), a cyclic adenosine monophosphate- (cAMP-) promoting agent causing positive changes in body composition in overweight and obese adult men, affects MCP-1 and GPR120 expression during an inflammatory response induced by lipopolysaccharide (LPS) in adipocytes, such as in an obese state...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/27873088/anti-inflammatory-and-insulin-sensitizing-effects-of-free-fatty-acid-receptors
#15
Junki Miyamoto, Mayu Kasubuchi, Akira Nakajima, Ikuo Kimura
Chronic low-grade inflammation in macrophages and adipose tissues can promote the development of obesity and type 2 diabetes. Free fatty acids (FFAs) have important roles in various tissues, acting as both essential energy sources and signaling molecules. FFA receptors (FFARs) can modulate inflammation in various types of cells and tissues; however the underlying mechanisms mediating these effects are unclear. FFARs are activated by specific FFAs; for example, GPR40 and GPR120 are activated by medium and long chain FFAs, GPR41 and GPR43 are activated by short chain FFAs, and GPR84 is activated by medium-chain FFAs...
November 22, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27853148/the-lipid-sensor-gpr120-promotes-brown-fat-activation-and-fgf21-release-from-adipocytes
#16
Tania Quesada-López, Rubén Cereijo, Jean-Valery Turatsinze, Anna Planavila, Montserrat Cairó, Aleix Gavaldà-Navarro, Marion Peyrou, Ricardo Moure, Roser Iglesias, Marta Giralt, Decio L Eizirik, Francesc Villarroya
The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning...
November 17, 2016: Nature Communications
https://www.readbyqxmd.com/read/27815121/discovery-of-benzofuran-propanoic-acid-gpr120-agonists-from-uhts-hit-to-mechanism-based-pharmacodynamic-effects
#17
Matthew Lombardo, Kate Bender, Clare London, Melissa Kirkland, Joel Mane, Michele Pachanski, Wayne Geissler, John Cummings, Bahanu Habulihaz, Taro E Akiyama, Jerry Di Salvo, Maria Madeira, Joanna Pols, Mary Ann Powles, Michael F Finley, Eric Johnson, Thomas Roussel, Victor N Uebele, Alejandro Crespo, Dennis Leung, Candice Alleyne, Dorina Trusca, Ying Lei, Andrew D Howard, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT)...
October 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27811230/in-vivo-activation-of-leukocyte-gpr120-ffar4-by-pufas-has-minimal-impact-on-atherosclerosis-in-ldl-receptor-knockout-mice
#18
Swapnil V Shewale, Amanda L Brown, Xin Bi, Elena Boudyguina, Janet K Sawyer, Martha A Alexander-Miller, John S Parks
G protein-coupled receptor (GPR)120/FFA receptor (FFAR)4 (GPR120/FFAR4) activation by n-3 PUFAs attenuates inflammation, but its impact on atherosclerosis is unknown. We determined whether in vivo activation of leukocyte GPR120/FFAR4 by n-3 versus n-6 PUFAs is atheroprotective. Leukocyte GPR120/FFAR4 WT or KO mice in the LDL receptor KO background were generated by bone marrow transplantation. Mice were fed one of the four atherogenic diets containing 0.2% cholesterol and 10% calories as palm oil (PO) + 10% calories as: 1) PO, 2) fish oil (FO; 20:5 n-3 and 22:6 n-3 enriched), 3) echium oil (EO; 18:4 n-3 enriched), or 4) borage oil (BO; 18:3 n-6 enriched) for 16 weeks...
January 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27807695/pharmacological-tool-compounds-for-the-free-fatty-acid-receptor-4-ffa4-gpr120
#19
Steffen V F Hansen, Trond Ulven
The free fatty acid receptor 4 (FFA4), also known as GPR120, is a G protein-coupled receptor that is activated by long-chain fatty acids and that has been associated with regulation of appetite, release of insulin controlling hormones, insulin sensitization, anti-inflammatory and potentially anti-obesity activity, and is progressively appearing as an attractive potential target for the treatment of metabolic dysfunctions such as obesity, type 2 diabetes and inflammatory disorders. Ongoing investigations of the pharmacological functions of FFA4 and validation of its potential as a therapeutic target depend critically on the appropriateness and quality of the available pharmacological probes or tool compounds...
November 3, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27779915/gpr119-a-major-enteroendocrine-sensor-of-dietary-triglyceride-metabolites-coacting-in-synergy-with-ffa1-gpr40
#20
Jeppe H Ekberg, Maria Hauge, Line V Kristensen, Andreas N Madsen, Maja S Engelstoft, Anna-Sofie Husted, Rasmus Sichlau, Kristoffer L Egerod, Pascal Timshel, Timothy J Kowalski, Fiona M Gribble, Frank Reiman, Harald S Hansen, Andrew D Howard, Birgitte Holst, Thue W Schwartz
Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice...
December 2016: Endocrinology
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