title: Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet.
abstract: OBJECTIVE
  Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.
  
  
  METHODS
  Male and female littermate Tlr2(+/+) and Tlr2(-/-) mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production.
  
  
  RESULTS
  While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2(-/-) mice were protected from the adverse effects of HFD compared with Tlr2(+/+) littermate controls. Female Tlr2(-/-) mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2(-/-) mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2(-/-) mice did not increase IL-1beta expression in response to a NEFA mixture, whereas Tlr2(+/+) control tissues did.
  
  
  CONCLUSIONS
  These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada V5Z 4H4. ehses@interchange.ubc.ca
authors.forename: J A
authors.initials: JA
authors.lastname: Ehses
authors.forename: D T
authors.initials: DT
authors.lastname: Meier
authors.forename: S
authors.initials: S
authors.lastname: Wueest
authors.forename: J
authors.initials: J
authors.lastname: Rytka
authors.forename: S
authors.initials: S
authors.lastname: Boller
authors.forename: P Y
authors.initials: PY
authors.lastname: Wielinga
authors.forename: A
authors.initials: A
authors.lastname: Schraenen
authors.forename: K
authors.initials: K
authors.lastname: Lemaire
authors.forename: S
authors.initials: S
authors.lastname: Debray
authors.forename: L
authors.initials: L
authors.lastname: Van Lommel
authors.forename: J A
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: O
authors.initials: O
authors.lastname: Tschopp
authors.forename: S M
authors.initials: SM
authors.lastname: Schultze
authors.forename: U
authors.initials: U
authors.lastname: Malipiero
authors.forename: H
authors.initials: H
authors.lastname: Esterbauer
authors.forename: H
authors.initials: H
authors.lastname: Ellingsgaard
authors.forename: S
authors.initials: S
authors.lastname: Rütti
authors.forename: F C
authors.initials: FC
authors.lastname: Schuit
authors.forename: T A
authors.initials: TA
authors.lastname: Lutz
authors.forename: M
authors.initials: M
authors.lastname: Böni-Schnetzler
authors.forename: D
authors.initials: D
authors.lastname: Konrad
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D002478:Cells, Cultured; D004041:Dietary Fats / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D051195:Toll-Like Receptor 2
references.citation: J Clin Endocrinol Metab. 2008 Oct;93(10):4065-74
references.pmid: 18664535
references.citation: Endocrinology. 2009 Dec;150(12):5218-29
references.pmid: 19819943
references.citation: Diabetes Care. 2008 Feb;31 Suppl 2:S161-4
references.pmid: 18227479
references.citation: Cell Metab. 2008 Oct;8(4):301-9
references.pmid: 18840360
references.citation: Cell Metab. 2006 Jul;4(1):13-24
references.pmid: 16814729
references.citation: N Engl J Med. 2007 Apr 12;356(15):1517-26
references.pmid: 17429083
references.citation: J Clin Invest. 2005 May;115(5):1111-9
references.pmid: 15864338
references.citation: J Clin Invest. 2002 May;109(10):1321-6
references.pmid: 12021247
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13998-4003
references.pmid: 19666548
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13163-8
references.pmid: 18719127
references.citation: Nat Rev Immunol. 2001 Nov;1(2):135-45
references.pmid: 11905821
references.citation: J Clin Invest. 2007 Jan;117(1):175-84
references.pmid: 17200717
references.citation: Arch Physiol Biochem. 2009 Oct;115(4):240-7
references.pmid: 19645635
references.citation: Diabetes Care. 2010 Apr;33(4):861-8
references.pmid: 20067962
references.citation: Diabetes. 2007 Aug;56(8):1986-98
references.pmid: 17519423
references.citation: J Clin Invest. 2006 Nov;116(11):3015-25
references.pmid: 17053832
references.citation: J Biol Chem. 2006 Sep 15;281(37):26865-75
references.pmid: 16798732
references.citation: Diabetologia. 2007 Jun;50(6):1267-76
references.pmid: 17426960
references.citation: Nat Med. 2009 Apr;15(4):373-4
references.pmid: 19350009
references.citation: Cell. 2009 Sep 4;138(5):961-75
references.pmid: 19737522
references.citation: Diabetologia. 2009 Mar;52(3):541-6
references.pmid: 19048227
references.citation: Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E740-7
references.pmid: 17090751
references.citation: Diabetes Care. 2009 Dec;32(12):2281-7
references.pmid: 19755625
references.citation: FASEB J. 2010 Mar;24(3):731-9
references.pmid: 19841034
references.citation: J Biol Chem. 2001 May 18;276(20):16683-9
references.pmid: 11278967
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: J Clin Invest. 2010 Jan;120(1):191-202
references.pmid: 19955656
references.citation: Diabetes. 2009 Nov;58(11):2525-35
references.pmid: 19690064
references.citation: Eur J Immunol. 2003 Nov;33(11):2998-3006
references.pmid: 14579268
references.citation: Diabetes. 2007 Jul;56(7):1761-72
references.pmid: 17456850
references.citation: J Biol Chem. 2004 Apr 23;279(17):16971-9
references.pmid: 14966134
references.citation: J Endocrinol. 2008 Dec;199(3):399-406
references.pmid: 18787058
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: J Biol Chem. 2007 Nov 30;282(48):35279-92
references.pmid: 17916553
references.citation: J Biol Chem. 2006 Oct 13;281(41):31002-11
references.pmid: 16880211
references.citation: Diabetes. 2007 Sep;56(9):2356-70
references.pmid: 17579207