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.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ssnyder@jhmi.edu
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Michael A
authors.initials: MA
authors.lastname: Koldobskiy
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Bello
authors.forename: Micah
authors.initials: M
authors.lastname: Maxwell
authors.forename: James J
authors.initials: JJ
authors.lastname: Potter
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Juluri
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.forename: Alex S
authors.initials: AS
authors.lastname: Huang
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Dailey
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Saleh
authors.forename: Adele M
authors.initials: AM
authors.lastname: Snowman
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Esteban
authors.initials: E
authors.lastname: Mezey
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D050156:Adipogenesis; D000375:Aging / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D004032:Diet; D011756:Diphosphates / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D011756:Diphosphates; C485444:Ihpk1 protein, mouse; D007295:Inositol Phosphates; D007328:Insulin; D007294:Inositol; D051057:Proto-Oncogene Proteins c-akt; D017856:Phosphotransferases (Phosphate Group Acceptor)