GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.
Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
Oh
Da Young
DY
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
Talukdar
Saswata
S
Bae
Eun Ju
EJ
Imamura
Takeshi
T
Morinaga
Hidetaka
H
Fan
WuQiang
W
Li
Pingping
P
Lu
Wendell J
WJ
Watkins
Steven M
SM
Olefsky
Jerrold M
JM
D041721:3T3-L1 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism; D002460:Cell Line; D004041:Dietary Fats / Q000378:metabolism; D019587:Dietary Supplements; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism; D007333:Insulin Resistance; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D004041:Dietary Fats; C498007:FFAR4 protein, mouse; D015525:Fatty Acids, Omega-3; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled
Diabetes. 2007 Apr;56(4):1034-41
17251275
FASEB J. 2009 Jun;23(6):1946-57
19211925
Biochem Soc Trans. 2005 Apr;33(Pt 2):423-7
15787620
Cell Metab. 2007 Nov;6(5):386-97
17983584
Diabetes. 2008 Dec;57(12):3239-46
18829989
Biochem Biophys Res Commun. 2007 Mar 9;354(2):591-7
17250804
Endocr Rev. 2000 Feb;21(1):90-113
10696571
J Cell Sci. 2002 Feb 1;115(Pt 3):455-65
11861753
J Lipid Res. 2003 Mar;44(3):479-86
12562875
Mol Cell. 2004 May 7;14(3):303-17
15125834
Nature. 2003 Mar 13;422(6928):173-6
12629551
Nat Immunol. 2006 Feb;7(2):139-47
16378096
Science. 1999 Jan 29;283(5402):655-61
9924018
Mol Pharmacol. 2001 Apr;59(4):758-64
11259620
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12011-6
17620599
J Clin Invest. 2008 Sep;118(9):2992-3002
18769626
J Mol Endocrinol. 2006 Jun;36(3):485-501
16720718
Diabetes. 1999 Jan;48(1):134-40
9892234
Br J Pharmacol. 2006 Jul;148(5):619-28
16702987
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Mol Cell Biol. 1999 Oct;19(10):6765-74
10490615
J Physiol Pharmacol. 2008 Aug;59 Suppl 2:251-62
18812643
Mol Endocrinol. 2005 Mar;19(3):722-31
15563546
J Biol Chem. 2007 Nov 30;282(48):35279-92
17916553
Nat Med. 2005 Jan;11(1):90-4
15619630
Am J Physiol. 1988 Dec;255(6 Pt 1):E769-74
3059816
Curr Opin Cell Biol. 2001 Apr;13(2):139-45
11248546
Arch Med Res. 1999 Nov-Dec;30(6):420-35
10714355
J Mol Biol. 2003 Feb 7;326(1):105-15
12547194
J Mol Neurosci. 2007 Sep;33(1):56-66
17901547
Cell Death Differ. 2006 May;13(5):816-25
16410796
J Biol Chem. 2006 Nov 10;281(45):34457-64
16966319
Gastroenterology. 2007 May;132(6):2169-80
17498510
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
J Biol Chem. 1997 Oct 31;272(44):27497-500
9346876