Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity

被引:1352
作者
Um, SH
Frigerio, F
Watanabe, M
Picard, F
Joaquin, M
Sticker, M
Fumagalli, S
Allegrini, PR
Kozma, SC
Auwerx, J
Thomas, G
机构
[1] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland
[2] ULP, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France
[3] Genopole Strasbourg, Inst Clin Souris, F-67404 Illkirch Graffenstaden, France
[4] Novartis Pharma AG, CH-4057 Basel, Switzerland
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature02866
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes(1). Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals(2), were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass(3). However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin(3), raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance(4,5). Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.
引用
收藏
页码:200 / 205
页数:6
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