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Protection against hepatic steatosis and systemic insulin resistance by liver‐specific depletion of p70 S6 kinase
Author(s) -
Bae Eunju,
Xu Jianfeng,
Olefsky Jerrold
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb133
Subject(s) - insulin resistance , steatosis , medicine , p70 s6 kinase 1 , endocrinology , lipogenesis , insulin , biology , impaired glucose tolerance , sterol regulatory element binding protein , metabolic syndrome , protein kinase b , diabetes mellitus , lipid metabolism , cholesterol , microbiology and biotechnology , phosphorylation , sterol
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 to 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 in 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