title: Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J mice.
abstract: Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6 β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark, the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway.
authors.forename: Even
authors.initials: E
authors.lastname: Fjære
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark, the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway.
authors.forename: Ulrike L
authors.initials: UL
authors.lastname: Aune
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Kristin
authors.initials: K
authors.lastname: Røen
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark, the Departments of Nutrition and.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Keenan
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Kamil
authors.initials: K
authors.lastname: Borkowski
authors.affiliation: the INSERM U1085-IRSET, Université de Rennes 1, Rennes, France, the Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Kristensen
authors.affiliation: the Section for Endocrinological Research, Department of Biomedical Sciences, University of 2200 Copenhagen, Copenhagen, Denmark.
authors.forename: Guy W
authors.initials: GW
authors.lastname: Novotny
authors.affiliation: the Section for Endocrinological Research, Department of Biomedical Sciences, University of 2200 Copenhagen, Copenhagen, Denmark, the Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Solna, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.affiliation: the Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom, and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hudson
authors.affiliation: the Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom, and.
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.affiliation: the Departments of Nutrition and.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Xi
authors.affiliation: the Departments of Nutrition and the United States Department of Agriculture-Agricultural Research Service-Western Human Nutrition Research Center, Davis, California 95616.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: the Departments of Nutrition and Internal Medicine, University of California, Davis, California 95616.
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.affiliation: the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Liaset
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark, kk@bio.ku.dk.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: From the Department of Biology, University of Copenhagen, 1165 Copenhagen, Denmark, the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway, lise.madsen@nifes.no.
authors.forename: Lise
authors.initials: L
authors.lastname: Madsen
mesh_terms: D000818:Animals; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D059305:Diet, High-Fat; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005951:Glucose Tolerance Test; D005990:Glycerol / Q000097:blood; D007213:Indomethacin / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000517:prevention & control*; D054883:Oxylipins / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016861:Cyclooxygenase Inhibitors; D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D054883:Oxylipins; D005990:Glycerol; D007213:Indomethacin
keywords: Adipose Tissue; Cyclooxygenase (COX); Cyclooxygenase Inhibitors; G Protein-coupled Receptor (GPCR); Glucose Intolerance; Insulin Resistance; Insulin Secretion
references.citation: ACS Med Chem Lett. 2010 Jul 02;1(7):345-9
references.pmid: 24900217
references.citation: Proc Natl Acad Sci U S A. 2011 May 31;108(22):9038-43
references.pmid: 21571638
references.citation: Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1323-32
references.pmid: 18812462
references.citation: Gastroenterol Jpn. 1980;15(5):433-8
references.pmid: 7439617
references.citation: Int J Cancer. 2011 Jul 15;129(2):331-45
references.pmid: 20857495
references.citation: J Biol Chem. 2011 Aug 12;286(32):28382-95
references.pmid: 21680746
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S74-9
references.pmid: 18997164
references.citation: J Biol Chem. 2011 Jan 7;286(1):889-98
references.pmid: 20961858
references.citation: Dev Cell. 2002 Jul;3(1):25-38
references.pmid: 12110165
references.citation: Nat Rev Immunol. 2011 Feb;11(2):98-107
references.pmid: 21233852
references.citation: Biochem Pharmacol. 2001 Dec 15;62(12):1587-95
references.pmid: 11755111
references.citation: Metabolism. 2000 Jul;49(7):839-44
references.pmid: 10909992
references.citation: Endocrinology. 1987 Oct;121(4):1221-6
references.pmid: 3308432
references.citation: Curr Pharm Des. 2008;14(12):1225-30
references.pmid: 18473870
references.citation: J Biol Chem. 2008 Mar 14;283(11):7196-205
references.pmid: 18070879
references.citation: ACS Med Chem Lett. 2013 May 9;4(5):441-445
references.pmid: 23687558
references.citation: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8977-82
references.pmid: 17416680
references.citation: Cell Metab. 2012 Dec 5;16(6):723-37
references.pmid: 23217255
references.citation: Cell. 2013 Feb 14;152(4):673-84
references.pmid: 23415219
references.citation: Diabetes. 2008 Sep;57(9):2432-7
references.pmid: 18559658
references.citation: Biochem Biophys Res Commun. 2007 Nov 9;363(1):37-43
references.pmid: 17825788
references.citation: Cell Metab. 2012 Jun 6;15(6):798-804
references.pmid: 22682220
references.citation: Trends Endocrinol Metab. 2013 Aug;24(8):398-407
references.pmid: 23631851
references.citation: Diabetes. 1980 May;29(5):379-82
references.pmid: 6769727
references.citation: FASEB J. 2004 Jul;18(10):1144-6
references.pmid: 15132977
references.citation: Receptor. 1994 Spring;4(1):17-23
references.pmid: 8038702
references.citation: J Lipid Res. 2011 May;52(5):991-1003
references.pmid: 21296957
references.citation: Am J Physiol Endocrinol Metab. 2012 May 15;302(9):E1097-112
references.pmid: 22338077
references.citation: Eur J Clin Invest. 2007 Mar;37(3):222-30
references.pmid: 17359490
references.citation: J Nutr. 2013 Sep;143(9):1367-75
references.pmid: 23843475
references.citation: J Clin Endocrinol Metab. 2000 Jul;85(7):2402-10
references.pmid: 10902785
references.citation: Am J Physiol Endocrinol Metab. 2001 Feb;280(2):E229-37
references.pmid: 11158925
references.citation: J Physiol. 2009 May 15;587(Pt 10):2387-97
references.pmid: 19332493
references.citation: Diabetes. 1998 Sep;47(9):1379-83
references.pmid: 9726224
references.citation: Nat Med. 2010 Apr;16(4):400-2
references.pmid: 20376053
references.citation: PLoS One. 2010 Jun 30;5(6):e11391
references.pmid: 20613988
references.citation: J Lipid Res. 2012 Aug;53(8):1662-9
references.pmid: 22628615
references.citation: Diabetes Care. 2001 Feb;24(2):362-5
references.pmid: 11213893
references.citation: Diabetes. 1992 Aug;41(8):927-35
references.pmid: 1628767
references.citation: Chem Biol. 1997 Dec;4(12):909-18
references.pmid: 9427656
references.citation: Science. 2010 May 28;328(5982):1158-61
references.pmid: 20448152
references.citation: Diabetologia. 2013 Feb;56(2):231-3
references.pmid: 23188391
references.citation: Arch Biochem Biophys. 2012 Jan 15;517(2):138-43
references.pmid: 22138222