Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3

Buffie Clodfelder-Miller,Patrizia De Sarno,Anna A Zmijewska,Ling Song,Richard S Jope

doi:10.1074/jbc.m508824200

Abstract

Insulin regulates the phosphorylation and activities of Akt and glycogen synthase kinase-3 (GSK3) in peripheral tissues, but in the brain it is less clear how this signaling pathway is regulated in vivo and whether it is affected by diabetes. We found that Akt and GSK3 are sensitive to glucose, because fasting decreased and glucose administration increased by severalfold the phosphorylation of Akt and GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain Akt and GSK3 phosphorylation also increased after streptozotocin administration (3 days), which increased blood glucose and depleted blood insulin, indicating regulation by glucose availability even with deficient insulin. Changes in Akt and GSK3 phosphorylation and activities in epididymal fat were opposite to those of brain after streptozotocin treatment. Streptozotocin-induced hyperglycemia and increased brain Akt and GSK3 phosphorylation were reversed by lowering blood glucose with insulin administration. Long term hyperglycemia also increased brain Akt and GSK3 phosphorylation, both 4 weeks after streptozotocin and in db/db insulin-resistant mice. Thus, the Akt-GSK3 signaling pathway is regulated in mouse brain in vivo in response to physiological and pathological changes in insulin and glucose.

Highlights

Tems within the brain either sense, or respond to, fluctuations in the circulating level of glucose or if they are buffered from such fluctuations
Brain Akt and glycogen synthase kinase-3 (GSK3) Are Dephosphorylated during Fasting—To test if the Akt-GSK3 coupled signaling pathway in mammalian brain is sensitive to peripheral glucose availability, we first examined if food withdrawal for 24 h affected the phosphorylation levels of Akt and GSK3 in mouse brain
These results show that the increased phosphorylation of Akt and GSK3 in the brain caused by streptozotocin-induced hyperglycemia could be rapidly reversed by lowering the blood glucose concentration. This investigation found a surprisingly strong role for physiological and pathological changes in the circulating concentration of glucose, in addition to insulin, in regulating the Akt-GSK3 signaling pathway in mouse brain. In both the cerebral cortex and the hippocampus, the phosphorylation states of Akt and GSK3 were found to be influenced by physiological fluctuations in the blood glucose concentration, by acutely administered glucose or insulin, by short term (3 days) and long term (4 weeks) hyperglycemia caused by pathological insulin depletion after streptozotocin administration, and by hyperglycemia linked to insulin resistance in type 2 diabetic db/db mice

Summary

Introduction

Tems within the brain either sense, or respond to, fluctuations in the circulating level of glucose or if they are buffered from such fluctuations. Akt often appears to be the predominant kinase mediating this phosphorylation of GSK3, this serine phosphorylation of GSK3 can be carried out by several other kinases under certain circumstances [14]. This coupling of Akt and GSK3 leads to inverse changes in their activities; when Akt activity is high it maintains GSK3 in a serine-phosphorylated inhibited state, and decreases in Akt activity lead to dephosphorylation and activation of GSK3. We report that in mouse brain in vivo the Akt-GSK3 signaling pathway senses physiological and pathological variations in circulating glucose levels with respondent changes in the regulatory phosphorylation states of Akt and GSK3

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Conclusion