Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance

Eun Ju Bae, Jianfeng Xu, Dayoung Oh, Gautam Bandyopadhyay, William S. Lagakos, Malik Keshwani, Jerrold M. Olefsky

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Obesity-associated hepatic steatosis is a manifestation of selective insulin resistance whereby lipogenesis remains sensitive to insulin but the ability of insulin to suppress glucose production is impaired. We created a mouse model of liver-specific knockdown of p70 S6 kinase (S6K) (L-S6K-KD) by systemic delivery of an adeno-associated virus carrying a shRNA for S6K and examined the effects on steatosis and insulin resistance. High fat diet (HFD) fed L-S6K-KD mice showed improved glucose tolerance and systemic insulin sensitivity compared with controls, with no changes in food intake or body weight. The induction of lipogenic gene expression was attenuated in the L-S6K-KD mice with decreased sterol regulatory element-binding protein (SREBP)-1c expression and mature SREBP-1c protein, as well as decreased steatosis on HFD. Our results demonstrate the importance of S6K: 1) as a modulator of the hepatic response to fasting/refeeding, 2) in the development of steatosis, and 3) as a key node in selective hepatic insulin resistance in obese mice.

Original languageEnglish (US)
Pages (from-to)18769-18780
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number22
DOIs
StatePublished - May 25 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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