Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats

Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. Systemic deletion of S6K protects against diet-induced obesity and enhances insulin sensitivity in mice. Herein, we present evidenc...

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Published in:The Journal of clinical investigation 2008-08, Vol.118 (8), p.2959-2968
Main Authors: Ono, Hiraku, Pocai, Alessandro, Wang, Yuhua, Sakoda, Hideyuki, Asano, Tomoichiro, Backer, Jonathan M, Schwartz, Gary J, Rossetti, Luciano
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Antibodies
Biomedical research
Care and treatment
Diet
Enzyme Activation
Genetic aspects
Glucose
Hypothalamus
Hypothalamus - metabolism
Insulin Resistance
Kinases
Liver - physiology
Male
Mediators
Metabolic diseases
Nutrients
Pathogenesis
Phosphorylation
Physiological aspects
Physiology
Rats
Rats, Sprague-Dawley
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Risk factors
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Summary:Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. Systemic deletion of S6K protects against diet-induced obesity and enhances insulin sensitivity in mice. Herein, we present evidence suggesting that hypothalamic S6K activation is involved in the pathogenesis of diet-induced hepatic insulin resistance. Extending previous findings that insulin suppresses hepatic glucose production (HGP) partly via its effect in the hypothalamus, we report that this effect was blunted by short-term high-fat diet (HFD) feeding, with concomitant suppression of insulin signaling and activation of S6K in the mediobasal hypothalamus (MBH). Constitutive activation of S6K in the MBH mimicked the effect of the HFD in normal chow-fed animals, while suppression of S6K by overexpression of dominant-negative S6K or dominant-negative raptor in the MBH restored the ability of MBH insulin to suppress HGP after HFD feeding. These results suggest that activation of hypothalamic S6K contributes to hepatic insulin resistance in response to short-term nutrient excess.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci34277