Pharmacological Characterization of the Receptor Mediating the Anorexigenic Action of the Octadecaneuropeptide: Evidence for an Endozepinergic Tone Regulating Food Intake

Abstract

Peptides of the endozepine family, including diazepam-binding inhibitor, the triakontatetraneuropeptide, and the octadecaneuropeptide (ODN), act through three types of receptors, that is, central-type benzodiazepine receptors (CBR), peripheral-type (mitochondrial) benzodiazepine receptors (PBR) and a metabotropic receptor positively coupled to phospholipase C via a pertussis toxin-sensitive G protein. We have previously reported that ODN exerts a potent anorexigenic effect in rat and we have found that the action of ODN is not affected by the mixed CBR/PBR agonist diazepam. In the present report, we have tested the possible involvement of the metabotropic receptor in the anorexigenic activity of ODN. Intracerebroventricular administration of the C-terminal octapeptide (OP) and its head-to-tail cyclic analog cyclo 1-8 OP (cOP) at a dose of 100 ng mimicked the inhibitory effect of ODN on food intake in fooddeprived mice. The specific CBR antagonist flumazenil and the PBR antagonist PK11195 did not prevent the effect of ODN, OP, and cOP on food consumption. In contrast, the selective metabotropic endozepine receptor antagonist cyclo 1-8 [DLeu 5 ]OP (100-1000 ng; cDLOP) suppressed the anorexigenic effect of ODN, OP, and cOP. At the highest concentration tested (1000 ng), cDLOP provoked by itself a significant increase in food intake. Taken together, the present results indicate that the anorexigenic effect of ODN and OP is mediated through activation of the metabotropic receptor recently characterized in astrocytes. The data also suggest that endogenous ODN, acting via this receptor, exerts an inhibitory tone on feeding behavior.

Macroglia-Microglia Interactions via TSPO Signaling Regulates Microglial Activation in the Mouse Retina

“…Because TSPO likely has distinct sites for ligandbinding and cholesterol binding (i.e., at the cholesterol recognition/interaction amino acid consensus [CRAC] domain; Li and Papadopoulos, 1998), the effects of ligand binding may act upstream to influence cholesterol binding and/or transport at the CRAC domain to facilitate subsequent neurosteroid production (Midzak et al, 2011). These results indicate that the therapeutic potential ascribed to synthetic ligands of TSPO (Rupprecht et al, 2010;Barron et al, 2013;Daugherty et al, 2013) may be extended to endogenous ligands such as TTN, and even possibly to ligands that modulate the function of the CRAC domain (Midzak et al, 2011;Lecanu et al, 2013), in measures to control microglia activation in chronic neuroinflammation.…”

“…Although TSPO expression has been primarily localized to microglia, astrocytes, and blood vessels in the normal and diseased brain (Stephenson et al, 1995;Cosenza-Nashat et al, 2009) and spinal cord (Daugherty et al, 2013), to our knowledge, its expression patterns in the developing and adult retina have not been described previously. Immunohistochemical analyses in CX3CR1…”

“…Synthetic ligands to TSPO (PK-11195, Ro5-4864, and etifoxine) have been shown to decrease microglia/macrophage activation in vitro (Choi et al, 2002; and in animal models of disease, including excitotoxic injury (Ryu et al, 2005), axonal injury (Girard et al, 2008), multiple sclerosis (Daugherty et al, 2013), and Alzheimer's disease (Barron et al, 2013). However, the functional significance of increased microglial TSPO expression and the signaling mechanisms involved in this response are unclear.…”

Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

“…Although there is clear evidence that the endozepine ODN is a potent anorexigenic peptide (De Mateos--Verchere et al 2001, Do Rego et al 2007, Matsuda et al 2007, the possible involvement of satiety signals in the control of DBI gene expression has never been reported. Therefore, in the present study, we have examined the effect of food deprivation as well as of insulin and leptin administration on DBI mRNA levels in astroglial cells.…”

“…In particular, astrocytes express the polypeptide diazepam-binding inhibitor (DBI) which generates through proteolytic cleavage several regulatory peptides including the anorexigenic octadecaneuropeptide (ODN;De Mateos-Verchere et al 2001, Do Rego et al 2007, Matsuda et al 2007. DBI is highly expressed in astroglial cells located in the hypothalamic regions which play a major role in the control of food intake, i.e.…”