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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
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
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
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
Swapnil V Shewale, Amanda L Brown, Xin Bi, Elena Boudyguina, Janet K Sawyer, Martha A Alexander-Miller, John S Parks
G protein-coupled receptor 120 (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 vs. n-6 PUFA 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...
November 3, 2016: Journal of Lipid Research
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
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
Irina G Tikhonova
Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors...
October 19, 2016: Handbook of Experimental Pharmacology
Brian M Moran, Aine M McKillop, Finbarr Pm O'Harte
Incretin based glucagon-like peptide-1 receptor (GLP-1R) agonists which target a G-protein coupled receptor (GPCR) are currently used in the treatment of type 2 diabetes. This review focuses on GPCRs from pancreatic β-cells, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, somatostatin, pancreatic polypeptide (PP), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin (OXM) and ghrelin receptors. In addition, fatty acids GPCRs are thought to have an increasing role in regulating peptide secretions namely short fatty acids GPCR (GPR41, GPR43), medium chain fatty acid GPCR (GPR84), long chain fatty acid GPCR (GPR40, GPR120) and cannabinoid-like GPCR (GPR55, GPR119)...
September 5, 2016: Current Opinion in Pharmacology
Jennifer Lee, Pedro M Moraes-Vieira, Angela Castoldi, Pratik Aryal, Eric U Yee, Christopher Vickers, Oren Parnas, Cynthia J Donaldson, Alan Saghatelian, Barbara B Kahn
We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment...
October 14, 2016: Journal of Biological Chemistry
Carlos M G Azevedo, Kenneth R Watterson, Ed T Wargent, Steffen V F Hansen, Brian D Hudson, Małgorzata A Kępczyńska, Julia Dunlop, Bharat Shimpukade, Elisabeth Christiansen, Graeme Milligan, Claire J Stocker, Trond Ulven
The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1...
October 13, 2016: Journal of Medicinal Chemistry
Kun Zhang, Zhimei Hu, Haixia Qi, Zhemin Shi, Yanan Chang, Qingbin Yao, Hongmei Cui, Lina Zheng, Yawei Han, Xiaohui Han, Zhen Zhang, Ting Chen, Wei Hong
Colorectal cancer (CRC) is one of the most common cancers leading to high mortality. However, long-term administration of anti-tumor therapy for CRC is not feasible due to the side effects. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that ω-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, ω-3 PUFAs promote phosphorylation and cytoplasmic retention of YAP and this effect was mediated by MST1/2 and LATS1, suggesting that the canonical Hippo Pathway is involved in ω-3 PUFAs function...
August 5, 2016: Oncotarget
Selvakumar Subramaniam, Mehmet Hakan Ozdener, Souleymane Abdoul-Azize, Katsuyoshi Saito, Bilal Malik, Guillaume Maquart, Toshihiro Hashimoto, Philippe Marambaud, Mourad Aribi, Michael G Tordoff, Philippe Besnard, Naim Akhtar Khan
Obesity is a major public health problem. An in-depth knowledge of the molecular mechanisms of oro-sensory detection of dietary lipids may help fight it. Humans and rodents can detect fatty acids via lipido-receptors, such as CD36 and GPR120. We studied the implication of the MAPK pathways, in particular, ERK1/2, in the gustatory detection of fatty acids. Linoleic acid, a dietary fatty acid, induced via CD36 the phosphorylation of MEK1/2-ERK1/2-ETS-like transcription factor-1 cascade, which requires Fyn-Src kinase and lipid rafts in human taste bud cells (TBCs)...
October 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tongxing Song, Yuanfei Zhou, Jian Peng, Ya-Xiong Tao, Yang Yang, Tao Xu, Jie Peng, Jiao Ren, Quanhang Xiang, Hongkui Wei
Numerous researches have demonstrated that GPR120 (also called FFAR4) exerts novel functions in insulin resistance and adipogenesis. However, the molecular mechanism of GPR120-mediated adipogenic differentiation is still unclear. This study was aimed to interpret the relevant function mechanism of GPR120 in the differentiation of 3T3-L1 adipocytes. The results showed that GPR120 expression was dramatically increased along with the adipogenic differentiation of 3T3-L1 adipocytes and the adipogenic ability was significantly inhibited in shGPR120-transfected cells...
October 15, 2016: Molecular and Cellular Endocrinology
Francisca Rodriguez-Pacheco, Carolina Gutierrez-Repiso, Sara Garcia-Serrano, Miguel A Alaminos-Castillo, Ailec Ho-Plagaro, Sergio Valdes, Juan Garcia-Arnes, Montserrat Gonzalo, Raul J Andrade, Francisco J Moreno-Ruiz, Alberto Rodriguez-Cañete, Abelardo Martinez-Ferriz, Eduardo Garcia-Fuentes
PURPOSE: This study examines whether G-protein coupled receptor 120 (GPR120) is involved in the pro-/anti-inflammatory effects of different types of fatty acids (FAs) in human visceral adipocytes, and whether these effects may be altered in obesity, a state with a chronic inflammation. METHODS: Pro-/anti-inflammatory effects of palmitic, oleic, linoleic and docosahexaenoic acids on human visceral adipocytes were tested in mature adipocytes from non-obese and morbidly obese (MO) subjects...
June 14, 2016: European Journal of Nutrition
Yasunori Konno, Shigeharu Ueki, Masahide Takeda, Yoshiki Kobayashi, Mami Tamaki, Yuki Moritoki, Hajime Oyamada, Masamichi Itoga, Hiroyuki Kayaba, Ayumi Omokawa, Makoto Hirokawa
[This corrects the article DOI: 10.1371/journal.pone.0120386.].
2016: PloS One
B Gao, Y-H Han, L Wang, Y-J Lin, Z Sun, W-G Lu, Y-Q Hu, J-Q Li, X-S Lin, B-H Liu, Q Jie, L Yang, Z-J Luo
Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs)...
2016: Cell Death & Disease
A Lamri, A Bonnefond, D Meyre, B Balkau, R Roussel, M Marre, P Froguel, F Fumeron
BACKGROUND AND AIMS: GPR120 (encoded by FFAR4) is a lipid sensor that plays an important role in the control of energy balance. GPR120 is activated by long chain fatty acids (FAs) including omega-3 FAs. In humans, the loss of function p.R270H variant of the gene FFAR4 has been associated with a lower protein activity, an increased risk of obesity and higher fasting plasma glucose levels. The aim of this study was to investigate whether p.R270H interacts with dietary fat intake to modulate the risk of type 2 diabetes (T2D, 198 incident; 368 prevalent cases) and overweight (787 incident and 2891 prevalent cases) in the prospective D...
October 2016: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
Frank Reimann, Fiona M Gribble
The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1, are secreted from intestinal K- and L cells, respectively, with the former being most abundant in the proximal small intestine, whereas the latter increase in number towards the distal gut. Although an overlap between K- and L cells can be observed immunohistochemically or in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority (>80%) of labeled cells seems to produce only one of these hormones...
April 2016: Journal of Diabetes Investigation
Kaori Fukushima, Kaede Takahashi, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
G-protein-coupled receptor 120 (GPR120) and GPR40 exhibit a variety of biological responses by the binding of free fatty acids. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a tumor promoting agent of skin carcinogenesis. It is known that TPA treatment stimulates cell motile activity of cancer cells, including melanoma cells. In the present study, we investigated whether GRP120 and GPR40 are involved in regulation of cell motile activity induced by TPA in two melanoma cell lines. A375 and G361 cells were treated with TPA at a concentration of 10 nM for 24 h...
June 17, 2016: Biochemical and Biophysical Research Communications
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