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Michael P Winters, Zhihua Sui, Mark Wall, Yuanping Wang, Joseph Gunnet, James Leonard, Hong Hua, Wen Yan, Arthur Suckow, Austin Bell, Wilmelenne Clapper, Celia Jenkinson, Peter Haug, Tatiana Koudriakova, Norman Huebert, William V Murray
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
February 8, 2018: Bioorganic & Medicinal Chemistry Letters
Lifu Xiao, Abdul K Parchur, Timothy A Gilbertson, Anhong Zhou
G-protein-coupled receptor 120 (GPR120), as a member of the rhodopsin family of G-protein-coupled receptors, has been shown to function as a sensor for dietary fat in the gustatory and digestive systems. Its specific role in the chemoreception of fatty acids, which is thought to be crucial in understanding the mechanism surrounding the control of fat intake and, accordingly, in the treatment of obesity, remains unclear. Here we report a novel surface-enhanced Raman spectroscopy (SERS)-fluorescence bimodal microscopic technique for detection and imaging of GPR120 in single living cells...
2018: Analytical Methods: Advancing Methods and Applications
Tomotaka Nagasawa, Hikaru Nakamichi, Yoichiro Hama, Shigeki Higashiyama, Yasuyuki Igarashi, Susumu Mitsutake
GPR120 is a receptor for long chain fatty acids and is expressed in small intestinal endocrine cells, L cells and adipose tissue. Activation of GPR120 promotes the secretion of incretin GLP-1, which is known to have effects on anti-metabolic syndrome. As such, GPR120 is a potential target of pharmaceuticals for type II diabetes. In this study, we performed ligand-screening for GPR120 on glycero- and sphingo-type lipids and their derivatives using a TGFα-shedding assay. We found that phytosphingosine (PHS) activates GPR120 in a manner comparable to the natural ligand α-linolenic acid (ALA) and superior to that of the synthetic ligand GW9508...
January 24, 2018: Journal of Biochemistry
Maaike Schilperoort, Andrea D van Dam, Geerte Hoeke, Irina G Shabalina, Anthony Okolo, Aylin C Hanyaloglu, Lea H Dib, Isabel M Mol, Natarin Caengprasath, Yi-Wah Chan, Sami Damak, Anne Reifel Miller, Tamer Coskun, Bharat Shimpukade, Trond Ulven, Sander Kooijman, Patrick Cn Rensen, Mark Christian
Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice...
January 17, 2018: EMBO Molecular Medicine
T Komprda, P Ondráčková, M Vícenová, V Rozíková, N Procházková, L Levá, M Faldyna
The present study tested a hypothesis that dietary fish oil (eicosapentaenoic acid+docosahexaenoic acid) in a commonly achievable dose ameliorates a systemic inflammation in pigs. Two groups of pigs of 16 animals each were fed a diet with either 2.5% of fish oil (F) or a control diet with 2.5% of palm oil (P). After 70 days of fattening, eight F and eight P pigs were challenged (F+; P+) i.v. by lipopolysaccharide. After 3 h, all pigs were sacrificed and blood, liver and visceral adipose tissue (VAT) samples were taken...
January 18, 2018: Animal: An International Journal of Animal Bioscience
Shenglong Zhu, Guangxiao Lin, Ci Song, Yikuan Wu, Ninghan Feng, Wei Chen, Zhao He, Yong Q Chen
Retinoic acid (RA), is a promising therapeutic agent for the treatment of breast cancer. However, metabolic disorders and drug resistance reduce the efficacy of RA. In this study, we found that RA and ω-3 polyunsaturated fatty acids (ω-3 PUFAs) synergistically induced cell death in vitro and in vivo and autophagy activation. Moreover, RA-induced hypercholesterolemia was completely corrected by ω-3 PUFA supplementation. In addition, we demonstrated that the effects of this combination on the autophagic flux were independent of the two major canonic regulatory complexes controlling autophagic vesicle formation...
December 12, 2017: Oncotarget
Kazuo Nakamoto, Koki Shimada, Shinichi Harada, Yasuko Morimoto, Akira Hirasawa, Shogo Tokuyama
Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases involving chronic accumulation of fat and inflammation, often leading to advanced fibrosis, cirrhosis and carcinoma. However, the pathological mechanism for this is unknown. GPR120/FFAR4 has been recognized as a functional fatty acid receptor and an attractive therapeutic target for metabolic diseases. In this study, we investigated the involvement of GPR120/FFAR4 in the pathogenesis of NASH. Mice fed with a 0.1% methionine and choline deficient high-fat (CDAHF) diet showed a significant increase in plasma aspartate transaminase and alanine transaminase levels, fatty deposition, inflammatory cell infiltration, and mild fibrosis...
February 5, 2018: European Journal of Pharmacology
Linda Sundström, Susanna Myhre, Monika Sundqvist, Andrea Ahnmark, William McCoull, Piotr Raubo, Sam D Groombridge, Magnus Polla, Ann-Christin Nyström, Lisbeth Kristensson, Mats Någård, Maria Sörhede Winzell
The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests...
2017: PloS One
Hanna Karakuła-Juchnowicz, Joanna Róg, Dariusz Juchnowicz, Justyna Morylowska-Topolska
G protein-coupled receptors (GPCRs) constitute a family of transmembrane proteins that mediate many cellular processes. GPR120/FFAR4, a receptor from this family that is activated by fatty acids, has received considerable attention recently. This paper presents a literature review concerning the role of GPR120 and its mechanism of action in animal and human studies as well as the potential use of GPR120 for the treatment of chronic diseases. Two electronic databases - Medline and Google Scholar - were searched for available studies addressing the review topic that were written in English and published from 2000 to June 2017...
November 19, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
Alexandre Moura-Assis, Milessa Silva Afonso, Vanessa de Oliveira, Joseane Morari, Gustavo Aparecido Dos Santos, Marcia Koike, Ana Maria Lottenberg, Rodrigo Ramos Catharino, Licio Augusto Velloso, Adelino Sanchez Ramos da Silva, L P de Moura, Eduardo Rochete Ropelle, José Rodrigo Pauli, Dennys Esper Corrêa Cintra
The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively...
March 2018: Journal of Nutritional Biochemistry
Saeromi Kang, Jin Huang, Bo-Kyung Lee, Young-Suk Jung, Eunok Im, Jung-Min Koh, Dong-Soon Im
Protective effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on non-alcoholic fatty liver disease has been demonstrated. FFA4 (also known as GPR120; a G protein-coupled receptor) has been suggested to be a target of n-3 PUFA. FFA4 expression in hepatocytes has also been reported from liver biopsies in child fatty liver patients. In order to assess the functional role of FFA4 in hepatic steatosis, we used an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis. FFA4 expression was confirmed in Hep3B and HepG2 human hepatoma cells...
February 2018: Biochimica et Biophysica Acta
Bastien Vallée Marcotte, Hubert Cormier, Iwona Rudkowska, Simone Lemieux, Patrick Couture, Marie-Claude Vohl
The objective was to test whether FFAR4 single nucleotide polymorphisms (SNPs) are associated with glycemic control-related traits in humans following fish oil supplementation. A total of 210 participants were given 3 g/day of omega-3 (n-3) fatty acids (FA) (1.9-2.2 g of eicosapentaenoic acid (EPA) and 1.1 g of docosahexaenoic acid (DHA)) during six weeks. Biochemical parameters were taken before and after the supplementation. Using the HapMap database and the tagger procedure in Haploview, 12 tagging SNPs in FFAR4 were selected and then genotyped using TaqMan technology...
November 6, 2017: Journal of Personalized Medicine
Yuko Kawabata, Fuminori Kawabata, Shotaro Nishimura, Shoji Tabata
It has been reported that a functional fat-taste receptor, GPR120, is present in chicken oral tissues, and that chickens can detect fat taste in a behavioral test. However, although triglycerides need to be digested to free fatty acids to be recognized by fat-taste receptors such as GPR120, it remains unknown whether lipase activities exist in chicken oral tissues. To examine this question, we first cloned another fat-taste receptor candidate gene, CD36, from the chicken palate. Then, using RT-PCR, we determined that GPR120 and CD36 were broadly expressed in chicken oral and gastrointestinal tissues...
October 25, 2017: Biochemical and Biophysical Research Communications
Shenglong Zhu, Xiaowei Jiang, Siyuan Jiang, Guangxiao Lin, Jianping Gong, Wei Chen, Zhao He, Yong Q Chen
Intake of ω-3 PUFAs reduces the frequency of breast cancer, and GPR120 receptor transduces ω-3 PUFAs signaling to increase insulin sensitivity in mice, but whether GPR120 mediates ω-3 PUFAs signaling to inhibit breast carcinogenesis is currently unknown. In the present study, we found that GPR120 is highly expressed in human breast cancerous tissues but not adjacent normal tissue. Knockdown of GPR120 by siRNA in breast cancer cells significantly reduced cell growth, and dramatically increased ω-3 FFA-induced cell growth inhibition and apoptosis...
October 5, 2017: Cell Biology International
Xuqing Zhang, Chaozhong Cai, Zhihua Sui, Mark Macielag, Yuanping Wang, Wen Yan, Arthur Suckow, Hong Hua, Austin Bell, Peter Haug, Wilma Clapper, Celia Jenkinson, Joseph Gunnet, James Leonard, William V Murray
We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120...
September 14, 2017: ACS Medicinal Chemistry Letters
Dong-Soon Im
Unsaturated long-chain fatty acids have been suggested to be beneficial in the context of cardiovascular disorders based in epidemiologic studies conducted in Greenland and Mediterranean. DHA and EPA are omega-3 polyunsaturated fatty acids that are plentiful in fish oil, and oleic acid is an omega-9 monounsaturated fatty acid, rich in olive oil. Dietary intake of these unsaturated long-chain fatty acids have been associated with insulin sensitivity and weight loss, which contrasts with the impairment of insulin sensitivity and weight gain associated with high intakes of saturated long-chain fatty acids...
September 8, 2017: Molecular Aspects of Medicine
Patricia Widmayer, Soumya Kusumakshi, Franziska A Hägele, Ulrich Boehm, Heinz Breer
During weaning, the ingested food of mouse pups changes from exclusively milk to solid food. In contrast to the protein- and carbohydrate-rich solid food, high fat milk is characterized primarily by fatty acids of medium chain length particularly important for the suckling pups. Therefore, it seems conceivable that the stomach mucosa may be specialized for detecting these important nutrients during the suckling phase. Here, we analyzed the expression of the G protein coupled receptors GPR84 and GPR120 (FFAR4), which are considered to be receptors for medium and long chain fatty acids (LCFAs), respectively...
2017: Frontiers in Physiology
Vasundhara Kain, Fei Liu, Veronika Kozlovskaya, Kevin A Ingle, Subhashini Bolisetty, Anupam Agarwal, Santosh Khedkar, Sumanth D Prabhu, Eugenia Kharlampieva, Ganesh V Halade
Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi-Lipoxin A4 (15-epi LXA4). However, the role of 15-epi LXA4 in post-MI acute inflammatory response and resolving phase is unclear. We hypothesize that liposomal fusion of 15-epi-LXA4 (Lipo-15-epi-LXA4) or free 15-epi-LXA4 will expedite the resolving phase in post-MI inflammation. 8 to 12-week-old male C57BL/6 mice were subjected to permanent coronary artery ligation...
August 30, 2017: Scientific Reports
Lirong Han, Shumin Song, Yabing Niu, Meng Meng, Chunling Wang
Objectives: To investigate the immunomodulatory effect and molecular mechanisms of Eicosapentaenoic acid (EPA, a typical kind of n-3PUFAs) on RAW264.7 cells. Methods: A variety of research methods, including the RAW264.7 cells culture, cell proliferation assays, morphologic observations, measurements of NO production, cytokine assays, nuclear protein extractions, western blot analyses and NF-κB p65 immunofluorescence assays were used in this study. Results: The results showed that EPA could increase the proliferation index and enhance the release of nitric oxide (NO) and cytokines in RAW264...
August 25, 2017: Nutrients
Laura Muredda, Małgorzata A Kępczyńska, Mohamed S Zaibi, Suliman Y Alomar, Paul Trayhurn
Regulation of the expression of GPCR fatty acid receptor genes has been examined in human adipocytes differentiated in culture. TNFα and IL-1β induced a marked reduction in GPR120 expression, mRNA level falling 17-fold at 24 h in adipocytes incubated with TNFα. In contrast, GPR84 mRNA was dramatically increased by these cytokines (>500-fold for IL-1β at 4 h); GPR41 expression was also stimulated. Rosiglitazone did not affect GPR84 expression, but GPR120 and GPR41 expression increased. Dexamethasone, insulin, linoleic and docosahexaenoic acids (DHA), and TUG891 (GPR120 agonist) had little effect on GPR120 and GPR84 expression...
August 24, 2017: Archives of Physiology and Biochemistry
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