Gliotransmission and Brain Glucose Sensing

Abstract

Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of endozepines in brain glucose sensing. First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist. The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway. Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis. Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders.

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…These findings are in line with growing literature showing that hypothalamic glial cells are involved in central glucose sensing and action (25)(26)(27)(28)(29). It is important to mention that we did not observe an increase in palmitate oxidation in response to AICAR in cortical astrocytes.…”

“…Hypothalamic neurons (24) and glia (25)(26)(27)(28)(29) are both able to sense glucose, and the importance of astroglia in central nutrient sensing has been recently emphasized (30). It is unclear if glucose modulation of LCFACoA metabolism occurs in neurons and/or astrocytes and whether or not such a feature distinguishes hypothalamic nuclei from other brain regions.…”

Hypothalamic Glucose-sensing: Role of Glia-to-Neuron Signaling

“…In addition, icv injection of ODN increases POMC mRNA level and decreases NPY mRNA level in the AN of the hypothalamus [ 69 ] , suggesting that the eff ect of ODN on food consumption is relayed by increased production of the anorexigenic POMC-derived peptide α-MSH and/or inhibition of the release of the orexigenic peptide NPY. As a matter of fact, recent data clearly demonstrate that the anorexigenic eff ect of an ODN analogue (ODN [11][12][13][14][15][16][17][18] , octadecaneuropeptide OP) is blocked by a selective antagonist of the α-MSH receptor [ 64 ] . Thus, although the AN neurons directly targeted by endozepines have not yet been identifi ed, it is actually clear that activation of α-MSH receptors is a necessary step in the anorexigenic eff ect of endozepines.…”

“…It was found that, in rats, an overnight fast markedly reduces DBI mRNA levels in cells bordering the third ventricle [ 55 , 64 ] . Central administration of glucose at the end of the fasting period partially restores DBI mRNA levels in tanycytes lining the mediane eminence and the AN, corresponding to β1 and β2 sub-populations [ 64 ] . Moreover, an increase in extracellular glucose is able to stimulate endozepine release from rat hypothalamic explants [ 64 ] .…”

“…Central administration of glucose at the end of the fasting period partially restores DBI mRNA levels in tanycytes lining the mediane eminence and the AN, corresponding to β1 and β2 sub-populations [ 64 ] . Moreover, an increase in extracellular glucose is able to stimulate endozepine release from rat hypothalamic explants [ 64 ] . Feeding experiments fi nally give strong support for a key role of endozepines in hypothalamic glucose-sensing as feeding behaviors elicited by either glucose or 2-DG are reversed by icv injection of ODN antagonist or agonist, respectively.…”