Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: involvement of astrocytes in cerebral glucose-sensing in rats.

Abstract

The detection of changes in glucose level constitutes the first step of the control of glucose homeostasis. Glucose sensors are therefore expected to be present in different parts of the body and particularly in the central nervous system. Some studies have already attempted to determine glucose-sensitive cerebral structures either after a glucoprivic stimulus or after prolonged hyperglycaemia. By analogy to beta cells, it was postulated that the glucose sensors in the brain could involve GLUT2, glucokinase and/or ATP-sensitive K(+) channels. Surprisingly, GLUT2 was mainly found in astrocytes. Thus, the aims of the present investigation were to determine, in awake rats: (i) the hypothalamic areas that respond to acute hyperglycaemic condition induced by an intracarotid injection of glucose and (ii) the involvement of astrocytes in glucose-sensing by the use of a glial drug, methionine sulfoximine. Rats were given intracarotid injections of glucose solution to trigger a transient insulin secretion without change in peripheral glycaemia, thus involving only central nervous regulation. Hypothalamic activation was determined by immunodetection of the immediate early gene c-fos protein. Acute glucose injection induces significant activation of arcuate and paraventricular nuclei. This stimulation mainly affects neurones in both nuclei, but also astrocytes in the former as illustrated by double immunohistochemistry (Fos and neuronal nuclei or glial fibrillary acidic protein). After specific impairment of astrocyte metabolism by methionine sulfoximine, cerebral activation disappears in the arcuate nucleus, correlated with the lack of cerebral glucose-induced insulin secretion. Therefore, arcuate and paraventricular hypothalamic nuclei are able to detect acute cerebral hyperglycaemia, leading to a peripheral stimulation of insulin secretion. Arcuate nucleus and more especially astrocytes in this nucleus play a pivotal role in glucose-sensing.