IKKβ suppression of TSC1 function links the mTOR pathway with insulin resistance

Dung Fang Lee, Hsu Ping Kuo, Chun Te Chen, Yongkun Wei, Chao Kai Chou, Jen Yu Hung, Chia Jui Yen, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

The proinflammatory cytokine TNFα 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 TNFα-mediated insulin resistance. In the present study, we demonstrated that TNFα-IKKβ-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 pIKKβ (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 IKKβ is a common molecular switch for both cancer pathogenesis and diet- and obesity-induced insulin resistance.

Original languageEnglish
Pages (from-to)633-638
Number of pages6
JournalInternational journal of molecular medicine
Volume22
Issue number5
DOIs
Publication statusPublished - 2008

All Science Journal Classification (ASJC) codes

  • Genetics

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