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Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population
  1. Marie A Vestmar1,2,
  2. Ehm A Andersson3,
  3. Charlotte R Christensen2,3,
  4. Maria Hauge1,2,
  5. Charlotte Glümer4,5,
  6. Allan Linneberg5,6,7,
  7. Daniel R Witte8,
  8. Marit E Jørgensen9,10,
  9. Cramer Christensen11,
  10. Ivan Brandslund12,13,
  11. Torsten Lauritzen8,
  12. Oluf Pedersen3,
  13. Birgitte Holst1,2,
  14. Niels Grarup3,
  15. Thue W Schwartz1,2,
  16. Torben Hansen3,10
  1. 1Department of Neuroscience and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
  2. 2Section for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  3. 3Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
  5. 5Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark
  6. 6Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
  7. 7Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  8. 8Section for General Practice, Department of Public Health, Aarhus University, Denmark
  9. 9Steno Diabetes Center, Gentofte, Denmark
  10. 10Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  11. 11Department of Internal Medicine and Endocrinology, SLB, Vejle Hospital, Vejle, Denmark
  12. 12Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark
  13. 13Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
  1. Correspondence to Dr Marie Aare Vestmar, Blegdamsvej 3B, Copenhagen N 2200, Denmark; mvestmar{at}sund.ku.dk

Abstract

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. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals.

Results p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect β-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901–71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05).

Conclusions We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

  • FFAR4
  • GPR120
  • Obesity
  • Genetics
  • Molecular genetics

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