TY - JOUR
T1 - Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance
AU - Bae, Eun Ju
AU - Xu, Jianfeng
AU - Oh, Dayoung
AU - Bandyopadhyay, Gautam
AU - Lagakos, William S.
AU - Keshwani, Malik
AU - Olefsky, Jerrold M.
PY - 2012/5/25
Y1 - 2012/5/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861564532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861564532&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.365544
DO - 10.1074/jbc.M112.365544
M3 - Article
C2 - 22493495
AN - SCOPUS:84861564532
SN - 0021-9258
VL - 287
SP - 18769
EP - 18780
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -