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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.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited in theNCBI Gene Expression Omnibus under accession number GSE32095.

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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.

Author information

Author notes

    • Atsuhiko Ichimura
    • , Akira Hirasawa
    • , Odile Poulain-Godefroy
    •  & Amélie Bonnefond

    These authors contributed equally to this work.

Affiliations

  1. Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan

    • Atsuhiko Ichimura
    • , Akira Hirasawa
    • , Takafumi Hara
    • , Ikuo Kimura
    • , Ning Liu
    • , Keiko Iida
    • , Kumiko Ayukawa
    • , Masato Takeuchi
    • , Kentaro Ozawa
    •  & Gozoh Tsujimoto
  2. Centre National de la Recherche Scientifique (CNRS)-Unité mixte de recherche (UMR) 8199, Lille Pasteur Institute, Lille 59000, France

    • Odile Poulain-Godefroy
    • , Amélie Bonnefond
    • , Loïc Yengo
    • , Audrey Leloire
    • , Hélène Choquet
    • , Cécile Lecoeur
    • , Sidonie Vivequin
    • , Anita Morandi
    • , Konstantinos Rouskas
    • , David Meyre
    • , Isabelle Wolowczuk
    •  & Philippe Froguel
  3. Lille Nord de France University, Lille 59000, France

    • Odile Poulain-Godefroy
    • , Amélie Bonnefond
    • , Loïc Yengo
    • , Audrey Leloire
    • , Hélène Choquet
    • , Cécile Lecoeur
    • , Sidonie Vivequin
    • , Anita Morandi
    • , Konstantinos Rouskas
    • , David Meyre
    • , Isabelle Wolowczuk
    •  & Philippe Froguel
  4. Institut National de la Santé et de la Recherche Médicale (Inserm)-UMR U866, Physiologie de la Nutrition, Bourgogne University, AgroSup Dijon, Dijon 21078, France

    • Philippe Besnard
  5. Inserm-U563, Children’s Hospital, Centre Hospitalier Universitaire, Toulouse 31000, France

    • Maithé Tauber
  6. Regional Centre for Juvenile Diabetes, Obesity and Clinical Nutrition, Verona 37134, Italy

    • Claudio Maffeis
    •  & Anita Morandi
  7. Department of Mother and Child, Biology-Genetics, Section of Paediatrics, University of Verona, Verona 37134, Italy

    • Claudio Maffeis
  8. Department of Clinical Sciences, La Sapienza University, Rome 00161, Italy

    • Raffaella Buzzetti
  9. Medical Research Council-HPA Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, St Mary’s campus, Imperial College London, London W2 1PG, UK

    • Paul Elliott
    •  & Marjo-Riitta Jarvelin
  10. National Public Health Institute, Biocenter Oulu, University of Oulu, Oulu 90220, Finland

    • Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  11. Institute of Clinical Medicine/Obstetrics and Gynecology, University of Oulu, Oulu 90220, Finland

    • Anneli Pouta
  12. Institute of Health Sciences, University of Oulu, Oulu 90220, Finland

    • Marjo-Riitta Jarvelin
  13. Center for Pediatric Research, Department of Women’s & Child Health, University of Leipzig, Leipzig 04317, Germany

    • Antje Körner
    •  & Wieland Kiess
  14. Inserm-U859, Lille Nord de France University, Lille 59000, France

    • Marie Pigeyre
    • , Roberto Caiazzo
    •  & François Pattou
  15. Lille University Hospital, Nutrition, Lille 59000, France

    • Marie Pigeyre
  16. Lille University Hospital, Endocrine Surgery, Lille 59000, France

    • Roberto Caiazzo
    •  & François Pattou
  17. Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium

    • Wim Van Hul
  18. Department of Endocrinology, Antwerp University Hospital, Antwerp 2650, Belgium

    • Luc Van Gaal
  19. Department of Surgery and Internal Medicine, Clinic Lindberg, Medical Department, Winterthur 8400, and University of Berne, Berne 3011, Switzerland

    • Fritz Horber
  20. Inserm-U780, Centre for research in Epidemiology and Population Health (CRESP), Villejuif 94800, France

    • Beverley Balkau
  21. Paris-Sud 11 University, Orsay 91405, France

    • Beverley Balkau
  22. Inserm-U690, Robert Debré hospital, Paris 75935, France

    • Claire Lévy-Marchal
  23. Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece

    • Konstantinos Rouskas
    •  & Anastasia Kouvatsi
  24. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen 45147, Germany

    • Johannes Hebebrand
    •  & Anke Hinney
  25. Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen 45122, Germany

    • Andre Scherag
  26. McMaster University, Hamilton, Ontario L8S 4L8, Canada

    • David Meyre
  27. Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan

    • Taka-aki Koshimizu
  28. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

    • Philippe Froguel

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gozoh Tsujimoto or Philippe Froguel.

Supplementary information

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  1. 1.

    Supplementary Information

    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.

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https://doi.org/10.1038/nature10798

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