title: Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion.
abstract: GPR40 (FFAR1) and GPR120 (FFAR4) are G-protein-coupled receptors (GPCRs) that are activated by long chain fatty acids (LCFAs). GPR40 is expressed at high levels in islets and mediates the ability of LCFAs to potentiate glucose-stimulated insulin secretion (GSIS). GPR120 is expressed at high levels in colon, adipose, and pituitary, and at more modest levels in pancreatic islets. The role of GPR120 in islets has not been explored extensively. Here, we confirm that saturated (e.g. palmitic acid) and unsaturated (e.g. docosahexaenoic acid (DHA)) LCFAs engage GPR120 and demonstrate that palmitate- and DHA-potentiated glucagon secretion are greatly reduced in isolated GPR120 KO islets. Remarkably, LCFA potentiated glucagon secretion is similarly reduced in GPR40 KO islets. Compensatory changes in mRNA expression of GPR120 in GPR40 KO islets, and vice versa, do not explain that LCFA potentiated glucagon secretion seemingly involves both receptors. LCFA-potentiated GSIS remains intact in GPR120 KO islets. Consistent with previous reports, GPR120 KO mice are hyperglycemic and glucose intolerant; however, our KO mice display evidence of a hyperactive counter-regulatory response rather than insulin resistance during insulin tolerance tests. An arginine stimulation test and a glucagon challenge confirmed both increases in glucagon secretion and liver glucagon sensitivity in GPR120 KO mice relative to WT mice. Our findings demonstrate that GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids and that an altered glucagon axis likely contributes to the impaired glucose homeostasis observed in GPR120 KO mice.
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121 suckowa@medimmune.com.
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Suckow
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: Wen
authors.initials: W
authors.lastname: Yan
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: Suhyoun
authors.initials: S
authors.lastname: Chon
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: James
authors.initials: J
authors.lastname: Leonard
authors.affiliation: From Janssen Research & Development, LLC, San Diego, California 92121.
authors.forename: Celia P
authors.initials: CP
authors.lastname: Briscoe
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C473034:FFAR1 protein, human; C519853:FFAR4 protein, human; C498007:FFAR4 protein, mouse; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D005934:Glucagon; D002118:Calcium
keywords: Alpha Cell; Fatty Acid; G Protein-coupled Receptor (GPCR); GPR120; GPR40; Glucagon; Lipid; Long Chain Fatty Acids; Pancreatic Islet; Polyunsaturated Fatty Acid (PUFA)
references.citation: Diabetes. 2011 Jan;60(1):239-47
references.pmid: 20971966
references.citation: Nature. 2012 Feb 19;483(7389):350-4
references.pmid: 22343897
references.citation: PLoS One. 2012;7(10):e46300
references.pmid: 23056280
references.citation: Br J Pharmacol. 2006 Jul;148(5):619-28
references.pmid: 16702987
references.citation: Biochem Pharmacol. 2009 Dec 15;78(12):1419-27
references.pmid: 19660440
references.citation: J Hepatol. 2014 Mar;60(3):625-32
references.pmid: 24262133
references.citation: Neurosci Lett. 2009 Jan 30;450(2):186-90
references.pmid: 19071193
references.citation: Diabetes. 2004 Nov;53(11):2836-43
references.pmid: 15504963
references.citation: Cell. 2010 Sep 3;142(5):687-98
references.pmid: 20813258
references.citation: Diabetes. 2007 Apr;56(4):1087-94
references.pmid: 17395749
references.citation: Diabetes. 2008 Nov;57(11):2999-3006
references.pmid: 18678612
references.citation: Diabetes. 2013 Oct;62(10):3316-23
references.pmid: 23818527
references.citation: Diabetes. 1997 Jul;46(7):1153-8
references.pmid: 9200650
references.citation: Diabetes. 1994 May;43(5):703-11
references.pmid: 8168648
references.citation: Lancet. 2012 Apr 14;379(9824):1403-11
references.pmid: 22374408
references.citation: Metabolism. 2005 Oct;54(10):1329-36
references.pmid: 16154432
references.citation: J Pharmacol Exp Ther. 2012 Feb;340(2):483-9
references.pmid: 22106100
references.citation: Endocrinology. 2008 Dec;149(12):6006-17
references.pmid: 18755801
references.citation: PLoS One. 2013 Jun 11;8(6):e65711
references.pmid: 23776533
references.citation: Cell Tissue Res. 2005 Nov;322(2):207-15
references.pmid: 16044321
references.citation: Diabetes Res Clin Pract. 2009 Sep;85(3):252-7
references.pmid: 19595468
references.citation: Cell Metab. 2010 Jun 9;11(6):543-553
references.pmid: 20519125
references.citation: Cell Metab. 2005 Apr;1(4):245-58
references.pmid: 16054069
references.citation: Cell. 2008 Oct 31;135(3):561-71
references.pmid: 18984166
references.citation: Mol Pharmacol. 2012 May;81(5):631-42
references.pmid: 22282525
references.citation: Diabetes. 2008 Sep;57(9):2432-7
references.pmid: 18559658
references.citation: Diabetes Obes Metab. 2011 Oct;13 Suppl 1:118-25
references.pmid: 21824265
references.citation: Diabetes Obes Metab. 2009 Nov;11 Suppl 4:10-20
references.pmid: 19817784
references.citation: Cell Metab. 2012 Jul 3;16(1):122-34
references.pmid: 22768844
references.citation: Nat Med. 2005 Jan;11(1):90-4
references.pmid: 15619630
references.citation: J Neurosci. 2010 Jun 23;30(25):8376-82
references.pmid: 20573884
references.citation: J Endocrinol. 2011 Aug;210(2):173-9
references.pmid: 21565851
references.citation: Biochem Biophys Res Commun. 2007 Mar 2;354(1):240-5
references.pmid: 17214971
references.citation: J Clin Invest. 2011 May;121(5):1858-70
references.pmid: 21490391