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Abstract

It is well known that the ω–3 fatty acids (ω–3-FAs; also known as n–3 fatty acids) can exert potent anti-inflammatory effects1,2,3,4. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω–3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity5,6,7. We reported that Gpr120 is the functional receptor for these fatty acids and that ω–3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner8. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4)9. However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein–coupled receptor10, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet–fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

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References

  1. 1.

    & Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease. Proc. Nutr. Soc. 66, 237–259 (2007).

  2. 2.

    et al. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J. Lipid Res. 44, 479–486 (2003).

  3. 3.

    , & Dietary omega-3 fats for treatment of inflammatory joint disease: efficacy and utility. Rheum. Dis. Clin. North Am. 34, 469–479 (2008).

  4. 4.

    Polyunsaturated fatty acids and inflammation. Biochem. Soc. Trans. 33, 423–427 (2005).

  5. 5.

    & Role of liver and plasma lipoproteins in selective transport of n-3 fatty acids to tissues: a comparative study of 14C-DHA and 3H-oleic acid tracers. J. Mol. Neurosci. 33, 56–66 (2007).

  6. 6.

    et al. n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator–activated receptor-α–dependent manner. Diabetes 56, 1034–1041 (2007).

  7. 7.

    , , , & Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J. Hypertens. 20, 1493–1499 (2002).

  8. 8.

    et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

  9. 9.

    et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012).

  10. 10.

    et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422, 173–176 (2003).

  11. 11.

    et al. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol. Pharmacol. 84, 710–725 (2013).

  12. 12.

    et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11, 90–94 (2005).

  13. 13.

    et al. Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn Schmiedebergs Arch. Pharmacol. 380, 247–255 (2009).

  14. 14.

    , , , & Discovery of a potent and selective GPR120 agonist. J. Med. Chem. 55, 4511–4515 (2012).

  15. 15.

    et al. Structure-activity relationships of GPR120 agonists based on a docking simulation. Mol. Pharmacol. 78, 804–810 (2010).

  16. 16.

    et al. Expression of the fatty acid receptor GPR120 in the gut of diet-induced-obese rats and its role in GLP-1 secretion. PLoS ONE 9, e88227 (2014).

  17. 17.

    et al. Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1. Mol. Cell. Endocrinol. 369, 119–129 (2013).

  18. 18.

    et al. GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 57, 1182–1191 (2014).

  19. 19.

    et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

  20. 20.

    et al. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab. 18, 759–766 (2013).

  21. 21.

    et al. S-nitrosylation–dependent inactivation of Akt/protein kinase B in insulin resistance. J. Biol. Chem. 280, 7511–7518 (2005).

  22. 22.

    et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147, 815–826 (2011).

  23. 23.

    et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).

  24. 24.

    et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010).

  25. 25.

    , , , & Increased macrophage migration into adipose tissue in obese mice. Diabetes 61, 346–354 (2012).

  26. 26.

    et al. NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell 155, 200–214 (2013).

  27. 27.

    et al. Lipidomics reveals a remarkable diversity of lipids in human plasma. J. Lipid Res. 51, 3299–3305 (2010).

  28. 28.

    et al. The fractalkine/CX3CR1 system regulates beta cell function and insulin secretion. Cell 153, 413–425 (2013).

  29. 29.

    et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011).

  30. 30.

    & Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

  31. 31.

    & Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

  32. 32.

    Reference Genome Group of the Gene Ontology Consortium. The Gene Ontology's Reference Genome Project: a unified framework for functional annotation across species. PLoS Comput. Biol. 5, e1000431 (2009).

  33. 33.

    & An overview of clustering applied to molecular biology. Methods Mol. Biol. 620, 369–404 (2010).

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Acknowledgements

This study was funded in part by grants to J.M.O. (DK033651, DK074868, DK063491 and DK09062) and D.Y.O. (P30 DK063491), a grant from Merck, Inc. to J.M.O. and D.Y.O., Austrian science fund (FWF Doktoratskolleg DK-MCD W1226 and the FWF project P24143) to J.G.B.-S., and a Marshall Plan Scholarship to A.R.P. We thank A. Tyler for editorial assistance and N. Sekiya for assistance with FACS analysis at the Veterans Affairs San Diego hospital, the University of California, San Diego (UCSD) Histology Core lab for technical help with processing liver specimens, and the UCSD Microscope Resource for microscopy analysis, which is funded by UCSD Neuroscience Microscopy Shared Facility Grant P30 NS047101.

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Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Da Young Oh
    • , Evelyn Walenta
    • , William S Lagakos
    • , Denise Lackey
    • , Ariane R Pessentheiner
    • , Roman Sasik
    • , Tyler J Chi
    • , Heekyung Chung
    • , Oswald Quehenberger
    • , Joanne McNelis
    •  & Jerrold M Olefsky
  2. Merck Research Laboratories, Kenilworth, New Jersey, USA.

    • Taro E Akiyama
    • , Jason M Cox
    • , Mary Ann Powels
    • , Jerry Di Salvo
    •  & Christopher Sinz
  3. Institute of Biochemistry, Graz University of Technology, Graz, Austria.

    • Ariane R Pessentheiner
    •  & Juliane G Bogner-Strauss
  4. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Nasun Hah
    •  & Ronald M Evans
  5. Lipomics Technologies, West Sacramento, California, USA.

    • Steven M Watkins
  6. Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.

    • Aaron M Armando
    •  & Oswald Quehenberger
  7. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Ronald M Evans

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Contributions

D.Y.O. designed the studies and performed most of the experiments; E.W. assisted with all animal experiments, FACS analysis and gene expression measurements; W.S.L. and D.L. conducted hyperinsulinemic-euglycemic clamps; T.E.A., J.M.C., M.A.P., J.D.S. and C.S. developed cpdA and provided initial screening data; A.R.P., H.C. and T.J.C. assisted with animal experiments and gene expression measurements; R.S. and N.H. carried out RNA-seq data analysis; S.M.W. performed lipomics analysis; A.M.A. and O.Q. performed eicosanoids measurements; J.M. conducted GSIS experiments; R.M.E. and J.G.B.-S. contributed to discussion; D.Y.O. and J.M.O. analyzed, interpreted data, supervised the project and co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Da Young Oh or Jerrold M Olefsky.

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DOI

https://doi.org/10.1038/nm.3614

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