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

SummaryThe 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.

Graphical AbstractFigure optionsDownload high-quality image (251 K)Download as PowerPoint slideHighlights
► Growth factor-induced inositol pyrophosphate (IP7) formation inhibits Akt activation
► IP7 acts at AKT's PH domain to block phosphorylation and membrane recruitment
► Mice deficient for the kinase that forms IP7, IP6K1, are resistant to obesity
► IP6K1 deletion improves glucose homeostasis in high-fat diet-fed mice