Summary 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 which regulates glucose homeostasis and protein translation respectively via the GSK3β and mTOR pathways. Thus Akt, mTOR and GSK3β signaling are dramatically augmented in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 impacts this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby impacting 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.

Glutathione (GSH) and bilirubin are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is effective because of the biosynthetic cycle wherein it is generated from biliverdin by biliverdin reductase (BVR). When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediately reduced by BVR to bilirubin. Why does the body employ both of these 2 distinct antioxidant systems? We show that the water-soluble GSH primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation. Mice with deletion of heme oxygenase-2, which generates biliverdin, display greater lipid than protein oxidation, while the reverse holds for GSH depletion. RNA interference depletion of BVR increases oxidation of lipids more than protein. Depletion of BVR or GSH augments cell death in an oxidant-specific fashion.apoptosis ͉ biliverdin ͉ cell death ͉ heme oxygenase ͉ neuroprotection

Background: D-serine is an endogenous coagonist of the N-methyl-D-aspartate subtype glutamate receptor. Genetic association studies have implicated genes coding for enzymes associated with Dserine metabolism in schizophrenia and bipolar disorder.