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Rôle des endozépines dans la régulation hypothalamique de l’homéostasie énergétique

Abstract : The term endozepine refers to a family of peptides including the diazepam-binding inhibitor (DBI) and its processing products, including the octadecaneuropeptide ODN (DBI33-50). Endozepins are true gliotransmitters since (i) DBI is expressed by CNS astroglial cells, (ii) their release is regulated by several neuropeptides, (iii) ODN decreases the expression of POMC and increases that of NPY at the arcuate nucleus, (iv) ODN exerts a strong anorectic effect in rodents. This effect is relayed by a metabotropic receptor distinct from the conventional benzodiazepine receptors. Some studies suggest that hypothalamic astroglial cells perceive certain circulating signals reflecting the energy status of the body. However, the nature of the signals involved in "glia-neuron" coupling remains unknown. All of these data suggest that the ODN could be a relay between the peripheral factors and the neuronal populations of the arcuate nucleus. We show for the first time that an acute 18-hour fast reduces the level of mRNAs encoding DBI in the astroglial cells of the medobasal hypothalamus. The insulin and leptin receptors are present on cells expressing DBI, however, the intraperitoneal injection of insulin or leptin is unable to reverse the effect of fasting. In a second step, we investigated the links that may exist between blood glucose and endozepines produced by astroglial cells. Central glucose injection increases the level of DBI-encoding transcripts at the periventricular zone of the hypothalamus of previously hungry rats, and the addition of glucose to the extracellular medium also stimulates the release of endozepines from hypothalamic explants. The anorexigenic effect of central or peripheral glucose injection in rats previously deprived of food is blocked by the icv injection of cyclo1-8 [DLeu5] OP, a metabotropic ODN antagonist analogue, while that the orexigenic effect of a central injection of 2-DG in normally fed rats is abolished by the co-injection of OP, an agonist analogue of this receptor. Finally, the anorexigenic effect of a central injection of glucose or OP is blocked by the co-injection of an MCR3 / 4 receptor antagonist, SHU-9119, demonstrating for the first time that endozepines, produced by glial cells, constitute an essential relay in the response of the melanocortic system to changes in blood glucose. Central injection of cyclo1-8 [dLeu5] OP results in increased blood glucose levels in normally fed rats while icv injection of ODN in hungry animals increases glucose tolerance, suggesting that the central endozepinergic system exerts an hypoglycemic tonic effect. Using the C6 cell line and the promoter / reporter strategy, we show the existence of a glucose response element in the proximal promoter of the DBI gene. Preliminary work conducted in vitro indicates that the activation of the DBI promoter by glucose is relayed via the hexosamine pathway, an ancillary pathway for glycolysis controlling the O-glycosylation of proteins. The immunohistochemical localization of O-glycosylated residues in the rat hypothalamus reveals the existence of intense labeling in glial cells expressing DBI, indicating that this pathway is functional in vivo. All of our work suggests that endozepines produced by hypothalamic glia play a key role in central glucose perception and participate in a feedback mechanism that controls glucose homeostasis in the body.
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Damien Lanfray. Rôle des endozépines dans la régulation hypothalamique de l’homéostasie énergétique. Sciences du Vivant [q-bio]. Université de Rouen Normandie, 2010. Français. ⟨tel-02295754⟩

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