Gliotransmission and brain glucose sensing: critical role of endozepines

Damien Lanfray; Sébastien Arthaud; Johanne Ouellet; Vincent Compère; Jean-Luc Do Rego; Jérôme Leprince; Benjamin Lefranc; Hélène Castel; Cynthia Bouchard; Boris Monge-Roffarello; Denis Richard; Georges Pelletier; Hubert Vaudry; Marie-Christine Tonon; Fabrice Morin

doi:10.2337/db11-0785

Gliotransmission and brain glucose sensing: critical role of endozepines

Diabetes. 2013 Mar;62(3):801-10. doi: 10.2337/db11-0785. Epub 2012 Nov 16.

Authors

Damien Lanfray¹, Sébastien Arthaud, Johanne Ouellet, Vincent Compère, Jean-Luc Do Rego, Jérôme Leprince, Benjamin Lefranc, Hélène Castel, Cynthia Bouchard, Boris Monge-Roffarello, Denis Richard, Georges Pelletier, Hubert Vaudry, Marie-Christine Tonon, Fabrice Morin

Affiliation

¹ INSERM U982, DC2N Laboratory of Neuronal and Neuroendocrine Cell Differentiation and Communication, Mont-Saint-Aignan, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Appetite Depressants / administration & dosage
Appetite Depressants / pharmacology
Appetite Regulation* / drug effects
Appetite Stimulants / administration & dosage
Appetite Stimulants / pharmacology
Appetitive Behavior / drug effects
Arcuate Nucleus of Hypothalamus / cytology
Arcuate Nucleus of Hypothalamus / drug effects
Arcuate Nucleus of Hypothalamus / metabolism
Diazepam Binding Inhibitor / agonists
Diazepam Binding Inhibitor / antagonists & inhibitors
Diazepam Binding Inhibitor / metabolism*
Feedback, Physiological* / drug effects
Gene Expression Regulation / drug effects
Glucose / administration & dosage
Glucose / metabolism*
Hypothalamus / cytology
Hypothalamus / drug effects
Hypothalamus / metabolism*
Injections, Intraventricular
Male
Nerve Tissue Proteins / agonists
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / metabolism
Neuroglia / drug effects
Neuroglia / metabolism*
Neuropeptides / antagonists & inhibitors
Neuropeptides / metabolism*
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism*
Protein Processing, Post-Translational
Rats
Rats, Wistar
Receptors, Melanocortin / antagonists & inhibitors
Receptors, Melanocortin / metabolism
Synaptic Transmission / drug effects
Tissue Culture Techniques

Substances

Appetite Depressants
Appetite Stimulants
Diazepam Binding Inhibitor
Nerve Tissue Proteins
Neuropeptides
Peptide Fragments
Receptors, Melanocortin
diazepam binding inhibitor (33-50)
Glucose