Open AccessIKKβ suppression of TSC1 function links the mTOR pathway with insulin resistance
Author(s) -
DungFang Lee,
Hsu Ping Kuo,
ChunTe Chen,
Yongkun Wei,
Chao-Kai Chou,
Jen Yu Hung,
Chia Jui Yen,
Mien Chie Hung
Publication year - 1998
Publication title -
international journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.048
H-Index - 90
eISSN - 1791-244X
pISSN - 1107-3756
DOI - 10.3892/ijmm_00000065
Subject(s) - pi3k/akt/mtor pathway , insulin resistance , irs1 , phosphorylation , insulin receptor , rptor , proinflammatory cytokine , protein kinase b , biology , p70 s6 kinase 1 , insulin , signal transduction , cancer research , endocrinology , microbiology and biotechnology , medicine , inflammation , immunology
The proinflammatory cytokine TNFalpha is one of the factors that links obesity-derived chronic inflammation with insulin resistance. Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1. It remains elusive that whether the mTOR pathway has a role in TNFalpha-mediated insulin resistance. In the present study, we demonstrated that TNFalpha-IKKbeta-mediated inactivation of TSC1 resulted in increasing phosphorylation of IRS1 serine 307 and serine 636/639, impaired insulin-induced glucose uptake, tyrosine phosphorylation of IRS1, and the association between IRS1 and PI3K p85. Furthermore, a higher expression of pIKKbeta (S181), pTSC1(S511), and pS6(S240/244) was found in livers obtained from both C57BL/6J mice on a high-fat diet and B6.V-Lepob/J mice. Collectively, dysregulation of the TSC1/ TSC2/mTOR signaling pathway by IKKbeta is a common molecular switch for both cancer pathogenesis and diet- and obesity-induced insulin resistance.