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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 are among the most efficacious stimulators of incretin secretion; however the relative importance of FFA1 (GPR40), FFA4 (GPR120) and GPR119 which all recognize triglyceride metabolites, i.e. LCFA and 2-MAG respectively, is still unclear. Here, we find all three receptors to be highly expressed and highly enriched in FACS-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the triglyceride-induced increase in plasma GIP was significantly reduced in FFA1 deficient mice (to 34% - mean of four 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...
October 25, 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)...
June 29, 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
Seong Hee Ahn, Sook-Young Park, Ji-Eun Baek, Su-Youn Lee, Wook-Young Baek, Sun-Young Lee, Young-Sun Lee, Hyun Ju Yoo, Hyeonmok Kim, Seung Hun Lee, Dong-Soon Im, Sun-Kyeong Lee, Beom-Jun Kim, Jung-Min Koh
Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4(-/-)) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1(Tg+)) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4(-/-) and fat-1(Tg+) mice over two generations to generate four genotypes of mice littermates: Ffar4(+/+);fat-1(Tg-), Ffar4(+/+);fat-1(Tg+), Ffar4(-/-);fat-1(Tg-), and Ffar4(-/-);fat-1(Tg+)...
July 2016: Endocrinology
Marie A Vestmar, Ehm A Andersson, Charlotte R Christensen, Maria Hauge, Charlotte Glümer, Allan Linneberg, Daniel R Witte, Marit E Jørgensen, Cramer Christensen, Ivan Brandslund, Torsten Lauritzen, Oluf Pedersen, Birgitte Holst, Niels Grarup, Thue W Schwartz, Torben Hansen
BACKGROUND: p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population. METHODS: Surface expression, Gq and Gi coupled signalling as well as β-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals...
September 2016: Journal of Medical Genetics
Junki Miyamoto, Sae Hasegawa, Mayu Kasubuchi, Atsuhiko Ichimura, Akira Nakajima, Ikuo Kimura
Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs' carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis...
2016: International Journal of Molecular Sciences
Adnan Munkarah, Ismail Mert, Jasdeep Chhina, Suhail Hamid, Laila Poisson, Sharon Hensley-Alford, Shailendra Giri, Ramandeep Rattan
OBJECTIVES: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. METHODS: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas...
April 2016: Gynecologic Oncology
Jia Yin, Haiying Li, Chengjie Meng, Dongdong Chen, Zhouqing Chen, Yibin Wang, Zhong Wang, Gang Chen
Omega-3 fatty acids have been reported to improve neuron functions during aging and in patients affected by mild cognitive impairment, and mediate potent anti-inflammatory via G protein-coupled receptor 120 (GPR120) signal pathway. Neuron dysfunction and inflammatory response also contributed to the progression of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was to examine the effects of omega-3 fatty acids on SAH-induced EBI. Two weeks before SAH, 30% Omega-3 fatty acids was administered by oral gavage at 1g/kg body weight once every 24h...
June 2016: International Journal of Biochemistry & Cell Biology
Tsubasa Kita, Yui Kadochi, Kaede Takahashi, Kaori Fukushima, Eri Yamasaki, Taiki Uemoto, Miku Hirane, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
Free fatty acids (FFAs) are dietary nutrients which mediate a variety of biological effects through binding to G-protein-coupled FFA receptors (FFARs). G-protein-coupled receptor 120 (GPR120) and GPR40 are identified as FFARs for long- and medium-chain fatty acids. Here we investigated whether GPR120 and GPR40 are involved in the acquisition of malignant properties in lung cancer cells. Three lung cancer RLCNR, LL/2 and A549 cells used in this study expressed GPR120 and GPR40 genes. The cell motile activities of all cells were significantly suppressed by a GPR40 antagonist GW1100...
March 15, 2016: Experimental Cell Research
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