title: Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, California 92093, USA.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Bae
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: William S
authors.initials: WS
authors.lastname: Lagakos
authors.forename: Malik
authors.initials: M
authors.lastname: Keshwani
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000517:prevention & control*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*
chemical_list: D019893:Ribosomal Protein S6 Kinases