Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice.
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.
Hosoi
Toru
T
Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toruh@hiroshima-u.ac.jp
Yokoyama
Shota
S
Matsuo
Suguru
S
Akira
Shizuo
S
Ozawa
Koichiro
K
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
D007328:Insulin; D020738:Leptin; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha
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