Inositol pyrophosphates inhibit akt signaling, thereby regulating insulin sensitivity and weight gain

Anutosh Chakraborty, Michael Koldobskiy, Nicholas T. Bello, Micah Maxwell, James John Potter, Krishna R. Juluri, David Maag, Seyun Kim, Alex S. Huang, Megan J. Dailey, Masoumeh Saleh, Adele M Snowman, Timothy H Moran, Esteban Mezey, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

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 GSK3β and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3β 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.

Original languageEnglish (US)
Pages (from-to)897-910
Number of pages14
JournalCell
Volume143
Issue number6
DOIs
StatePublished - Dec 10 2010

Fingerprint

Diphosphates
Inositol
Weight Gain
Insulin Resistance
Obesity
Insulin
White Adipose Tissue
Protein-Serine-Threonine Kinases
Protein Biosynthesis
High Fat Diet
Knockout Mice
Phosphorylation
Skeletal Muscle
Homeostasis
Nutrition
Medical problems
Glucose
Liver
Muscle
Aging of materials

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Inositol pyrophosphates inhibit akt signaling, thereby regulating insulin sensitivity and weight gain. / Chakraborty, Anutosh; Koldobskiy, Michael; Bello, Nicholas T.; Maxwell, Micah; Potter, James John; Juluri, Krishna R.; Maag, David; Kim, Seyun; Huang, Alex S.; Dailey, Megan J.; Saleh, Masoumeh; Snowman, Adele M; Moran, Timothy H; Mezey, Esteban; Snyder, Solomon H.

In: Cell, Vol. 143, No. 6, 10.12.2010, p. 897-910.

Research output: Contribution to journalArticle

Chakraborty, Anutosh ; Koldobskiy, Michael ; Bello, Nicholas T. ; Maxwell, Micah ; Potter, James John ; Juluri, Krishna R. ; Maag, David ; Kim, Seyun ; Huang, Alex S. ; Dailey, Megan J. ; Saleh, Masoumeh ; Snowman, Adele M ; Moran, Timothy H ; Mezey, Esteban ; Snyder, Solomon H. / Inositol pyrophosphates inhibit akt signaling, thereby regulating insulin sensitivity and weight gain. In: Cell. 2010 ; Vol. 143, No. 6. pp. 897-910.
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