The Experts below are selected from a list of 1350 Experts worldwide ranked by ideXlab platform
Akira Hirasawa - One of the best experts on this subject based on the ideXlab platform.
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colocalization of GPR120 and anterior pituitary hormone producing cells in female japanese black cattle
Journal of Reproduction and Development, 2020Co-Authors: Akira Hirasawa, Sho Nakamura, Kohei Noda, Masafumi Miwa, Shiori Minabe, Teruki Hagiwara, Shuichi Matsuyama, Ryutaro MoriyamaAbstract:: Negative energy balance in domestic animals suppresses their reproductive function. These animals commonly use long-chain fatty acids (LCFAs) from adipocytes as an energy source under states of malnutrition. The G-protein coupled receptor, GPR120, is a specific receptor for LCFAs, but its role in reproductive function remains unknown in domestic animals. The purpose of this study was to examine whether GPR120 is involved in the reproductive system of cattle. GPR120 mRNA expression was evaluated in brain, pituitary, and ovarian tissue samples by RT-PCR. GPR120 gene expression was detected with high intensity only in the anterior pituitary sample, and GPR120-immunoreactive cells were found in the anterior pituitary gland. Double immunohistochemistry of GPR120 in the anterior pituitary hormone-producing cells, such as gonadotropes, thyrotropes, lactotropes, somatotropes, and corticotropes, was performed to clarify the distribution of GPR120 in the anterior pituitary gland of ovariectomized heifers. Luteinizing hormone β subunit (LHβ)- and follicle-stimulating hormone β subunit (FSHβ)-immunoreactive cells demonstrated GPR120 immunoreactivity at 80.7% and 85.9%, respectively. Thyrotropes, lactotropes, somatotropes, and corticotropes coexpressed GPR120 at 21.1%, 5.4%, 13.6%, and 14.5%, respectively. In conclusion, the present study suggests that GPR120 in the anterior pituitary gland might mediate LCFA signaling to regulate gonadotrope functions, such as hormone secretion or production, in cattle.
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dha supplementation prevent the progression of nash via GPR120 signaling
European Journal of Pharmacology, 2018Co-Authors: Kazuo Nakamoto, Akira Hirasawa, Koki Shimada, Shinichi Harada, Yasuko Morimoto, Shogo TokuyamaAbstract:Abstract 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. Docosahexaenoic acid (DHA, GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in the liver tissues and prevented fibrosis in the wild type (WT) mice fed CDAHF diet, but not GPR120/FFAR4 deficient (GPR120KO) mice. GPR120KO mice fed CDAHF diet showed increment of the number of crown like structures and the immunoreactivity for F4/80 positive cells, and increased TNF-α mRNA in the liver compared to WT mice fed CDAHF diet. GPR120 KO mice fed CDAHF diet showed more severe liver inflammation than that of WT mice fed CDAHF diet, but not fibrosis. Our findings suggest that DHA supplementation could be prevented the development of NASH via GPR120/FFAR4 signaling. Furthermore, decrease of GPR120/FFAR4 signaling could be facilitated an inflammatory response in the process of NASH progression.
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abstract 307 GPR120 ffar4 activation by fatty acid 16 4 n 3 plays a key role in resistance to chemotherapy
Cancer Research, 2016Co-Authors: Julia M Houthuijzen, Akira Hirasawa, Brian D Hudson, Ilse Oosterom, Laura G M Daenen, Chelsea M Mclean, Steffen V F Hansen, Marijn T M Van Jaarsveld, Daniel S Peeper, Sahar Jafari SadatmandAbstract:Although chemotherapy is designed to eradicate tumor cells it also has a significant impact on normal tissues. These host-responses can have large effects on the efficacy of treatment and overall survival. Fatty acids are increasingly recognized to play important signaling roles. 12-S-HHT and 16:4(n-3) are two platinum-induced fatty acids (PIFAs) that induce systemic resistance to a broad range of DNA-damaging chemotherapeutics. PIFAs exert their chemoprotective effect on tumor cells via an indirect mechanism involving splenic F4/80 + /CD11b low macrophages. Here we identified GPR120 on mouse and human splenic macrophages as the relevant receptor for 16:4(n-3). GPR120 (FFAR4) is a free fatty acid receptor that binds medium- to long-chain fatty acids and omega-3 fatty acids and is involved in anti-inflammatory response and metabolic control. Although both GPR40 (FFAR1) and GPR120 can be activated by 16:4(n-3) in vitro, only inhibition or genetic loss of GPR120 was able to block 16:4(n-3)-mediated chemoresistance in vivo. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA 2 activity in splenic macrophages resulting in the production and secretion of resistance-inducing lysophosphatidylcholine 24:1 (LPC(24:1)). Taken together, we identified a novel function for GPR120. Activation by 16:4(n-3) leads to enhanced cPLA 2 activity and production of LPC(24:1) resulting in chemotherapy resistance. Citation Format: Julia Houthuijzen, Ilse Oosterom, Brian Hudson, Akira Hirasawa, Laura Daenen, Chelsea McLean, Steffen Hansen, Marijn van Jaarsveld, Daniel Peeper, sahar Jafari Sadatmand, Jeanine Roodhart, Chris van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest. GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 307.
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the oral lipid sensor GPR120 is not indispensable for the orosensory detection of dietary lipids in mice
Journal of Lipid Research, 2015Co-Authors: Deborah Ancel, Akira Hirasawa, Gozoh Tsujimoto, Arnaud Bernard, Selvakumar Subramaniam, Toshihiro Hashimoto, Patricia Passillydegrace, Naimakhtar Khan, Philippe BesnardAbstract:Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4, in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the “taste of fat”, the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological [i.e., immunohistochemical staining of circumvallate papillae (CVP)], behavioral (i.e., two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies [i.e., calcium imaging in freshly isolated taste bud cells (TBCs)], we show that absence of GPR120 in the oral cavity was not associated with changes in i) gross anatomy of CVP, ii) LCFA-mediated increases in intracellular calcium levels ([Ca2+]i), iii) preference for oily and LCFA solutions and iv) conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca2+]i triggered by grifolic acid, a specific GPR120 agonist, was dramatically curtailed when the GPR120 gene was lacking. Taken together, these data demonstrate that activation of lingual GPR120 and preference for fat are not connected, suggesting that GPR120 expressed in TBCs is not absolutely required for oral fat detection in mice
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regulation of energy homeostasis via GPR120
Frontiers in Endocrinology, 2014Co-Authors: Atsuhiko Ichimura, Takafumi Hara, Akira HirasawaAbstract:Free fatty acids (FFAs) are fundamental units of key nutrients. FFAs exert various biological functions, depending on the chain length and degree of desaturation. Recent studies have shown that several FFAs act as ligands of G-protein-coupled receptors (GPCRs), activate intracellular signaling and exert physiological functions via these GPCRs. GPR120 (also known as free fatty acid receptor 4, FFAR4) is activated by unsaturated medium- to long-chain FFAs and has a critical role in various physiological homeostasis mechanisms such as incretin hormone secretion, food preference, anti-inflammation and adipogenesis. Recent studies showed that a lipid sensor GPR120 has a key role in sensing dietary fat in white adipose tissue and regulates the whole body energy homeostasis in both humans and rodents. Genetic study in human identified the loss-of-functional mutation of GPR120 associated with obesity and insulin resistance. In addition, dysfunction of GPR120 has been linked as a novel risk factor for diet-induced obesity. This review aims to provide evidence from the recent development in physiological function of GPR120 and discusses its functional roles in regulation of energy homeostasis and its potential as drug targets.
Gozoh Tsujimoto - One of the best experts on this subject based on the ideXlab platform.
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the oral lipid sensor GPR120 is not indispensable for the orosensory detection of dietary lipids in mice
Journal of Lipid Research, 2015Co-Authors: Deborah Ancel, Akira Hirasawa, Gozoh Tsujimoto, Arnaud Bernard, Selvakumar Subramaniam, Toshihiro Hashimoto, Patricia Passillydegrace, Naimakhtar Khan, Philippe BesnardAbstract:Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4, in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the “taste of fat”, the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological [i.e., immunohistochemical staining of circumvallate papillae (CVP)], behavioral (i.e., two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies [i.e., calcium imaging in freshly isolated taste bud cells (TBCs)], we show that absence of GPR120 in the oral cavity was not associated with changes in i) gross anatomy of CVP, ii) LCFA-mediated increases in intracellular calcium levels ([Ca2+]i), iii) preference for oily and LCFA solutions and iv) conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca2+]i triggered by grifolic acid, a specific GPR120 agonist, was dramatically curtailed when the GPR120 gene was lacking. Taken together, these data demonstrate that activation of lingual GPR120 and preference for fat are not connected, suggesting that GPR120 expressed in TBCs is not absolutely required for oral fat detection in mice
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free fatty acids and protein kinase c activation induce GPR120 free fatty acid receptor 4 phosphorylation
European Journal of Pharmacology, 2014Co-Authors: Omar B Sanchezreyes, Akira Hirasawa, Gozoh Tsujimoto, Teresa M Romeroavila, Jean A Castillobadillo, Yoshinori Takei, Rafael Villalobosmolina, Adolfo J GarciasainzAbstract:Abstract GPR120, free fatty acid receptor 4, is a recently deorphanized G protein-coupled receptor that seems to play cardinal roles in the regulation of metabolism and in the pathophysiology of inflammatory and metabolic disorders. In the present work a GPR120-Venus fusion protein was expressed in HEK293 Flp-In T-REx cells and its function (increase in intracellular calcium) and phosphorylation were studied. It was observed that the fusion protein migrated in sodium dodecyl sulfate-polyacrylamide gels as a band with a mass of ≈70–75 kDa, although other bands of higher apparent weight (>130 kDa) were also detected. Cell stimulation with docosahexaenoic acid or α-linolenic acid induced concentration-dependent increases in intracellular calcium and GPR120 phosphorylation. Activation of protein kinase C with phorbol esters also induced a marked receptor phosphorylation but did not alter the ability of 1 µM docosahexaenoic acid to increase the intracellular calcium concentration. Phorbol ester-induced GPR120 phosphorylation, but not that induced with docosahexaenoic acid, was blocked by protein kinase C inhibitors (bis-indolyl-maleimide I and Go 6976) suggesting that conventional kinase isoforms mediate this action. The absence of effect of protein kinase C inhibitors on agonist-induced GPR120 phosphorylation indicates that this kinase does not play a major role in agonist-induced receptor phosphorylation. Docosahexaenoic acid action was associated with marked GPR120 internalization whereas that induced with phorbol esters was smaller at early times.
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ffa1 selective agonistic activity based on docking simulation using ffa1 and GPR120 homology models
British Journal of Pharmacology, 2013Co-Authors: Masato Takeuchi, Akira Hirasawa, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Tatsuya Hirano, Gozoh TsujimotoAbstract:BACKGROUND AND PURPOSE The free fatty acid FFA1 receptor and GPR120 are GPCRs whose endogenous ligands are medium- and long-chain FFAs, and they are important in regulating insulin and GLP-1 secretion respectively. Given that the ligands of FFA1 receptor and GPR120 have similar properties, selective pharmacological tools are required to study their functions further. EXPERIMENTAL APPROACH We used a docking simulation approach using homology models for each receptor. Biological activity was assessed by phosphorylation of ERK and elevation of intracellular calcium ([Ca2+]i) in cells transfected with FFA1 receptor or GPR120. Insulin secretion from murine pancreatic beta cells (MIN6) was also measured. KEY RESULTS Calculated hydrogen bonding energies between a series of synthetic carboxylic acid compounds and the homology models of the FFA1 receptor and GPR120, using docking simulations, correlated well with the effects of the compounds on ERK phosphorylation in transfected cells (R2= 0.65 for FFA1 receptor and 0.76 for GPR120). NCG75, the compound with the highest predicted selectivity for FFA1 receptors from this structure-activity relationship analysis, activated ERK and increased [Ca2+]i as potently as the known FFA1 receptor-selective agonist, Compound 1. Site-directed mutagenesis analysis based on the docking simulation showed that different amino acid residues were important for the recognition and activation by FFA1 receptor agonists. Moreover, NCG75 strongly induced ERK and [Ca2+]i responses, and promoted insulin secretion from MIN6 cells, which express endogenous FFA1 receptors. CONCLUSION AND IMPLICATIONS A docking simulation approach using FFA1 receptor and GPR120 homology models could be useful in predicting FFA1 receptor-selective agonists.
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structure activity relationships of GPR120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
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novel selective ligands for free fatty acid receptors GPR120 and gpr40
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Takafumi Hara, Tetsuya Adachi, Taka-aki Koshimizu, Akira Hirasawa, Toshihiro Hashimoto, Keiko Sadakane, Chisato Itsubo, Yoshinori Asakawa, Gozoh TsujimotoAbstract:GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
Takafumi Hara - One of the best experts on this subject based on the ideXlab platform.
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regulation of energy homeostasis via GPR120
Frontiers in Endocrinology, 2014Co-Authors: Atsuhiko Ichimura, Takafumi Hara, Akira HirasawaAbstract:Free fatty acids (FFAs) are fundamental units of key nutrients. FFAs exert various biological functions, depending on the chain length and degree of desaturation. Recent studies have shown that several FFAs act as ligands of G-protein-coupled receptors (GPCRs), activate intracellular signaling and exert physiological functions via these GPCRs. GPR120 (also known as free fatty acid receptor 4, FFAR4) is activated by unsaturated medium- to long-chain FFAs and has a critical role in various physiological homeostasis mechanisms such as incretin hormone secretion, food preference, anti-inflammation and adipogenesis. Recent studies showed that a lipid sensor GPR120 has a key role in sensing dietary fat in white adipose tissue and regulates the whole body energy homeostasis in both humans and rodents. Genetic study in human identified the loss-of-functional mutation of GPR120 associated with obesity and insulin resistance. In addition, dysfunction of GPR120 has been linked as a novel risk factor for diet-induced obesity. This review aims to provide evidence from the recent development in physiological function of GPR120 and discusses its functional roles in regulation of energy homeostasis and its potential as drug targets.
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ffa1 selective agonistic activity based on docking simulation using ffa1 and GPR120 homology models
British Journal of Pharmacology, 2013Co-Authors: Masato Takeuchi, Akira Hirasawa, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Tatsuya Hirano, Gozoh TsujimotoAbstract:BACKGROUND AND PURPOSE The free fatty acid FFA1 receptor and GPR120 are GPCRs whose endogenous ligands are medium- and long-chain FFAs, and they are important in regulating insulin and GLP-1 secretion respectively. Given that the ligands of FFA1 receptor and GPR120 have similar properties, selective pharmacological tools are required to study their functions further. EXPERIMENTAL APPROACH We used a docking simulation approach using homology models for each receptor. Biological activity was assessed by phosphorylation of ERK and elevation of intracellular calcium ([Ca2+]i) in cells transfected with FFA1 receptor or GPR120. Insulin secretion from murine pancreatic beta cells (MIN6) was also measured. KEY RESULTS Calculated hydrogen bonding energies between a series of synthetic carboxylic acid compounds and the homology models of the FFA1 receptor and GPR120, using docking simulations, correlated well with the effects of the compounds on ERK phosphorylation in transfected cells (R2= 0.65 for FFA1 receptor and 0.76 for GPR120). NCG75, the compound with the highest predicted selectivity for FFA1 receptors from this structure-activity relationship analysis, activated ERK and increased [Ca2+]i as potently as the known FFA1 receptor-selective agonist, Compound 1. Site-directed mutagenesis analysis based on the docking simulation showed that different amino acid residues were important for the recognition and activation by FFA1 receptor agonists. Moreover, NCG75 strongly induced ERK and [Ca2+]i responses, and promoted insulin secretion from MIN6 cells, which express endogenous FFA1 receptors. CONCLUSION AND IMPLICATIONS A docking simulation approach using FFA1 receptor and GPR120 homology models could be useful in predicting FFA1 receptor-selective agonists.
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dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Akira Hirasawa, Takafumi Hara, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human. The G-protein-coupled receptor GPR120 is a receptor for free fatty acids, and is involved in homeostasis mechanisms such as fat-cell generation and the regulation of appetite. Here it is shown that without GPR120, mice on a high-fat diet develop obesity, glucose intolerance and fatty liver. In humans, GPR120 expression in adipose tissue is shown to be significantly elevated in obesity. The authors also identify a mutation that inhibits GPR120 signalling activity and is associated with an increased risk for obesity in Europeans. Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes1,2,3,4. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases3,5,6,7,8,9,10,11,12,13. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference5,6,14,15,16. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
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dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Akira Hirasawa, Takafumi Hara, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human.
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structure activity relationships of GPR120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
Ikuo Kimura - One of the best experts on this subject based on the ideXlab platform.
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ffa1 selective agonistic activity based on docking simulation using ffa1 and GPR120 homology models
British Journal of Pharmacology, 2013Co-Authors: Masato Takeuchi, Akira Hirasawa, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Tatsuya Hirano, Gozoh TsujimotoAbstract:BACKGROUND AND PURPOSE The free fatty acid FFA1 receptor and GPR120 are GPCRs whose endogenous ligands are medium- and long-chain FFAs, and they are important in regulating insulin and GLP-1 secretion respectively. Given that the ligands of FFA1 receptor and GPR120 have similar properties, selective pharmacological tools are required to study their functions further. EXPERIMENTAL APPROACH We used a docking simulation approach using homology models for each receptor. Biological activity was assessed by phosphorylation of ERK and elevation of intracellular calcium ([Ca2+]i) in cells transfected with FFA1 receptor or GPR120. Insulin secretion from murine pancreatic beta cells (MIN6) was also measured. KEY RESULTS Calculated hydrogen bonding energies between a series of synthetic carboxylic acid compounds and the homology models of the FFA1 receptor and GPR120, using docking simulations, correlated well with the effects of the compounds on ERK phosphorylation in transfected cells (R2= 0.65 for FFA1 receptor and 0.76 for GPR120). NCG75, the compound with the highest predicted selectivity for FFA1 receptors from this structure-activity relationship analysis, activated ERK and increased [Ca2+]i as potently as the known FFA1 receptor-selective agonist, Compound 1. Site-directed mutagenesis analysis based on the docking simulation showed that different amino acid residues were important for the recognition and activation by FFA1 receptor agonists. Moreover, NCG75 strongly induced ERK and [Ca2+]i responses, and promoted insulin secretion from MIN6 cells, which express endogenous FFA1 receptors. CONCLUSION AND IMPLICATIONS A docking simulation approach using FFA1 receptor and GPR120 homology models could be useful in predicting FFA1 receptor-selective agonists.
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dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Akira Hirasawa, Takafumi Hara, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human.
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dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Nature, 2012Co-Authors: Atsuhiko Ichimura, Akira Hirasawa, Takafumi Hara, Odile Poulaingodefroy, Amelie Bonnefond, Loic Yengo, Ikuo KimuraAbstract:Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human. The G-protein-coupled receptor GPR120 is a receptor for free fatty acids, and is involved in homeostasis mechanisms such as fat-cell generation and the regulation of appetite. Here it is shown that without GPR120, mice on a high-fat diet develop obesity, glucose intolerance and fatty liver. In humans, GPR120 expression in adipose tissue is shown to be significantly elevated in obesity. The authors also identify a mutation that inhibits GPR120 signalling activity and is associated with an increased risk for obesity in Europeans. Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes1,2,3,4. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases3,5,6,7,8,9,10,11,12,13. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference5,6,14,15,16. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
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structure activity relationships of GPR120 agonists based on a docking simulation
Molecular Pharmacology, 2010Co-Authors: Akira Hirasawa, Tetsuya Adachi, Takafumi Hara, Ikuo Kimura, Takeo Awaji, Masaji Ishiguro, Takayoshi Suzuki, Naoki Miyata, Gozoh TsujimotoAbstract:GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds ( R2 = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
Marta Giralt - One of the best experts on this subject based on the ideXlab platform.
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the lipid sensor GPR120 promotes brown fat activation and fgf21 release from adipocytes
Nature Communications, 2016Co-Authors: Tania Quesadalopez, Ruben Cereijo, Jean Valery Turatsinze, Anna Planavila, Montserrat Cairo, Aleix Gavaldanavarro, Marion Peyrou, Ricardo Moure, Roser Iglesias, Marta GiraltAbstract: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. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.
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The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes
Nature Communications, 2016Co-Authors: Tania Quesada-lópez, Ruben Cereijo, Jean Valery Turatsinze, Anna Planavila, Montserrat Cairo, Marion Peyrou, Ricardo Moure, Roser Iglesias, Aleix Gavaldà-navarro, Marta GiraltAbstract:GPR120 is a G-protein-coupled receptor that binds polyunsaturated fatty acids. Here, the authors show that GPR120 is upregulated in brown fat in cold-exposed mice, and mediates thermogenic activation of brown fat via a mechanism that, at least in part, depends on the release of the adipokine FGF21. 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. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.
