Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain

被引：288

作者：

Chakraborty, Anutosh ^{[1
]}

Koldobskiy, Michael A. ^{[1
]}

Bello, Nicholas T. ^{[2
]}

Maxwell, Micah ^{[1
]}

Potter, James J. ^{[3
]}

Juluri, Krishna R. ^{[1
]}

Maag, David ^{[1
]}

Kim, Seyun ^{[1
]}

Huang, Alex S. ^{[1
]}

Dailey, Megan J. ^{[2
]}

Saleh, Masoumeh ^{[1
]}

Snowman, Adele M. ^{[1
]}

Moran, Timothy H. ^{[2
]}

Mezey, Esteban ^{[3
]}

Snyder, Solomon H. ^{[1
,2
,4
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

来源：

CELL | 2010年 / 143卷 / 06期

关键词：

PROTEIN-KINASE-B; MICE LACKING; PPAR-GAMMA; FAT MASS; PHOSPHORYLATION; ACTIVATION; MTOR; PHOSPHOINOSITIDES; RESISTANCE; MEMBRANE;

D O I：

10.1016/j.cell.2010.11.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3 beta and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3b signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.

引用

页码：897 / 910

页数：14

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