title: Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice.
abstract: BACKGROUND
  Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR) 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD)-induced obesity.
  
  
  RESULTS
  In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP), which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD.
  
  
  CONCLUSIONS
  The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toruh@hiroshima-u.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoi
authors.forename: Shota
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Suguru
authors.initials: S
authors.lastname: Matsuo
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha
references.citation: Science. 1981 May 8;212(4495):628-35
references.pmid: 6261329
references.citation: Nat Med. 2005 Feb;11(2):183-90
references.pmid: 15685173
references.citation: Cell Metab. 2009 Feb;9(2):125-39
references.pmid: 19187771
references.citation: Mol Pharmacol. 2008 Dec;74(6):1610-9
references.pmid: 18755873
references.citation: Science. 2008 Aug 1;321(5889):691-6
references.pmid: 18669862
references.citation: J Biol Chem. 2001 May 18;276(20):16683-9
references.pmid: 11278967
references.citation: Science. 1993 Jan 1;259(5091):87-91
references.pmid: 7678183
references.citation: Nature. 1979 Nov 29;282(5738):503-5
references.pmid: 116135
references.citation: Immunity. 1998 Jul;9(1):143-50
references.pmid: 9697844
references.citation: Science. 1997 Nov 28;278(5343):1612-5
references.pmid: 9374458
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: Nat Med. 2005 Feb;11(2):191-8
references.pmid: 15685170
references.citation: J Biol Chem. 2005 Jun 10;280(23):21763-72
references.pmid: 15826936
references.citation: J Biol Chem. 1993 Dec 15;268(35):26055-8
references.pmid: 8253716
references.citation: Biochem Biophys Res Commun. 1994 Feb 28;199(1):144-6
references.pmid: 8123006
references.citation: J Clin Invest. 2002 Oct;110(7):905-11
references.pmid: 12370266
references.citation: Diabetes. 2007 Aug;56(8):1986-98
references.pmid: 17519423
references.citation: Nat Rev Immunol. 2008 Dec;8(12):923-34
references.pmid: 19029988
references.citation: J Clin Invest. 2006 Nov;116(11):3015-25
references.pmid: 17053832
references.citation: J Clin Invest. 1993 Aug;92(2):883-93
references.pmid: 8349823
references.citation: J Biol Chem. 1994 Oct 21;269(42):26396-401
references.pmid: 7929360
references.citation: Oncogene. 1990 Mar;5(3):387-96
references.pmid: 1690380
references.citation: Diabetologia. 2007 Jun;50(6):1267-76
references.pmid: 17426960
references.citation: Nat Rev Drug Discov. 2009 May;8(5):386-98
references.pmid: 19404312
references.citation: Cell Metab. 2009 Oct;10(4):249-59
references.pmid: 19808018
references.citation: Endocrinology. 1992 Jan;130(1):43-52
references.pmid: 1727716
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: Biochem Biophys Res Commun. 2007 Mar 2;354(1):45-9
references.pmid: 17210129
references.citation: J Biol Chem. 2004 Oct 29;279(44):45803-9
references.pmid: 15331609
references.citation: Cell. 2000 Oct 13;103(2):239-52
references.pmid: 11057897
references.citation: Mol Cell. 1998 Aug;2(2):253-8
references.pmid: 9734363
references.citation: Immunity. 1999 Jul;11(1):115-22
references.pmid: 10435584