A novel IKKβ inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance

Junji Kamon, Toshimasa Yamauchi, Susumu Muto, Sato Takekawa, Yusuke Ito, Yusuke Hada, Wataru Ogawa, Akiko Itai, Masato Kasuga, Kazuyuki Tobe, Takashi Kadowaki

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IκB kinase β (IKKβ) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKA y mice that were fed a high-fat diet. The IKKβ inhibitor cancelled the TNFα-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKCλ (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion.

Original languageEnglish
Pages (from-to)242-248
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume323
Issue number1
DOIs
StatePublished - 2004/10/08

Keywords

  • Adipocytes
  • Adiponectin
  • Akt activity
  • IKKβ inhibitor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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