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

Anutosh Chakraborty; Michael A. Koldobskiy; Nicholas T. Bello; Micah Maxwell; James J. 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

doi:10.1016/j.cell.2010.11.032

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

Anutosh Chakraborty, Michael A. Koldobskiy, Nicholas T. Bello, Micah Maxwell, James J. 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 journal › Article › peer-review

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 language	English (US)
Pages (from-to)	897-910
Number of pages	14
Journal	Cell
Volume	143
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2010.11.032
State	Published - Dec 10 2010
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2010.11.032

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Chakraborty, A., Koldobskiy, M. A., Bello, N. T., Maxwell, M., Potter, J. J., Juluri, K. R., Maag, D., Kim, S., Huang, A. S., Dailey, M. J., Saleh, M., Snowman, A. M., Moran, T. H., Mezey, E., & Snyder, S. H. (2010). Inositol pyrophosphates inhibit akt signaling, thereby regulating insulin sensitivity and weight gain. Cell, 143(6), 897-910. https://doi.org/10.1016/j.cell.2010.11.032

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

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.",

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

note = "Funding Information: We thank Robert Luo for providing the pCDNA-TOPO-V5/His full-length and ΔPH Akt constructs; Susan Aja for the Oxymax experiments; Cory Brayton for histological analysis; Molee Chakraborty, Nadine Forbes, Kent Werner, and Gary Ho for technical support; and Asif Mustafa for helpful discussions. This work was supported by U.S. Public Health Service Grants MH18501 and DA-000266 and Research Scientist Award DA00074 (to S.H.S.). ",

year = "2010",

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doi = "10.1016/j.cell.2010.11.032",

language = "English (US)",

volume = "143",

pages = "897--910",

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T1 - Inositol pyrophosphates inhibit akt signaling, thereby regulating insulin sensitivity and weight gain

AU - Chakraborty, Anutosh

AU - Koldobskiy, Michael A.

AU - Bello, Nicholas T.

AU - Maxwell, Micah

AU - Potter, James J.

AU - Juluri, Krishna R.

AU - Maag, David

AU - Kim, Seyun

AU - Huang, Alex S.

AU - Dailey, Megan J.

AU - Saleh, Masoumeh

AU - Snowman, Adele M.

AU - Moran, Timothy H.

AU - Mezey, Esteban

AU - Snyder, Solomon H.

N1 - Funding Information: We thank Robert Luo for providing the pCDNA-TOPO-V5/His full-length and ΔPH Akt constructs; Susan Aja for the Oxymax experiments; Cory Brayton for histological analysis; Molee Chakraborty, Nadine Forbes, Kent Werner, and Gary Ho for technical support; and Asif Mustafa for helpful discussions. This work was supported by U.S. Public Health Service Grants MH18501 and DA-000266 and Research Scientist Award DA00074 (to S.H.S.).

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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.

AB - 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.

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

Abstract

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