Abstract
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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Change history
28 February 2012
The Supplementary Tables were missing from the original supplementary information file and have since been added.
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Acknowledgements
We are indebted to all subjects who participated in these studies. In Japan, the study was supported in part by research grants from the Japan Society for the Promotion of Science; the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Japan Science and Technology Agency; and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program), initiated by the Council for Science and Technology Policy. A.I. is a fellow of the Japan Society for the Promotion of Science. A.B. is a fellow of the EU-funded EUROCHIP consortium. In France, the study was supported by le Conseil Régional Nord Pas de Calais/FEDER and the Agence Nationale de la Recherche (Programme de Recherche en Nutrition et Alimentation, SensoFAT). The Northern Finland Birth Cohort Studies 1986 received financial support from the Academy of Finland, the University Hospital of Oulu (Finland), the University of Oulu (Finland), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), and the Medical Research Council (G0500539, G0600705, PrevMetSyn/SALVE). We thank the ABOS consortium and the CIC-CCPPRB (Lille CHRU) team for their help in sample handling and clinical data collection. We are grateful to M. Deweirder and F. Allegaert for human DNA bank management.
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A.I., A. Hirasawa, O.P.-G. and A.B. are equally contributing first authors. G.T. and P.F. had the ideas for the mouse and human projects, respectively. A.I., A. Hirasawa, A.B., P.F. and G.T. drafted the manuscript. O.P.-G., H.C., D.M. and I.W. edited the manuscript and contributed to discussions. A. Hirasawa and G.T. designed the mouse research. A.I., A. Hirasawa, K.I. and G.T. created Gpr120-mutant mice. A.I., A. Hirasawa, A. Körner, T.H., I.K., T.-a.K., K.A., M. Takeuchi, K.O., N.L. and G.T. conducted biochemical and histochemical analyses for the mouse study. A.I. and A. Hirasawa performed bioinformatic analysis for the mouse study. L.Y. and C.L. performed the statistical analyses, and A.B. contributed to statistical analyses for the human study. O.P.-G. and I.W. designed the human expression gene study. A.L. performed the human expression gene study. H.C. and S.V. performed GPR120 sequencing and variant genotyping, respectively. P.B., M. Tauber, C.M., A.M., R.B., P.E., M.-R.J., W.V.H., L.V.G., F.H., B.B., C.L.-M., K.R., A. Kouvatsi and F.P. contributed to cohort-study samples and researched data.
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This file contains Supplementary Figures 1-7 with legends and Supplementary Tables 1-7. The Supplementary Tables were missing from the original file posted on line and were added on 28 February 2012. (PDF 2380 kb)
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Ichimura, A., Hirasawa, A., Poulain-Godefroy, O. et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012). https://doi.org/10.1038/nature10798
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DOI: https://doi.org/10.1038/nature10798
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