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Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity. We carried out a combination of physiological, pharmacological, and molecular analyses together to dissect the underlying mechanisms of endozepine-induced hypophagia. To evaluate the potential anti-obesity effect of endozepines, different model of obesity were used, i.e., ob/ob and diet-induced obese mice. We show that the intracerebral administration of endozepines enhances satiety by targeting anorexigenic brain circuitry and induces STAT3 phosphorylation, a hallmark of leptin signaling. Strikingly, endozepines are entirely ineffective at reducing food intake in the presence of a circulating leptin antagonist and in leptin-deficient mice (ob/ob) but potentiate the reduced food intake and weight loss induced by exogenous leptin administration in these animals. Endozepines reversed high fat diet-induced obesity by reducing food intake and restored leptin-induced STAT3 phosphorylation in the hypothalamus. Interestingly, we observed that glucose and insulin synergistically enhance tanycytic endozepine expression and release. Finally, endozepines, which induce ERK activation necessary for leptin transport into the brain in cultured tanycytes, require tanycytic leptin receptor expression to promote STAT3 phosphorylation in the hypothalamus. Our data identify endozepines as potential anti-obesity compounds in part through the modulation of the LepR-ERK-dependent tanycytic leptin shuttle. [ABSTRACT FROM AUTHOR]

Endozepines are endogenous ligands for the benzodiazepine receptors and also target a still unidentified GPCR. The endozepine octadecaneuropeptide (ODN), an endoproteolytic processing product of the diazepam-binding inhibitor (DBI) was recently shown to be involved in food intake control as an anorexigenic factor through ODN-GPCR signaling and mobilization of the melanocortinergic signaling pathway. Within the hypothalamus, the DBI gene is mainly expressed by non-neuronal cells such as ependymocytes, tanycytes, and protoplasmic astrocytes, at levels depending on the nutritional status. Administration of ODN C-terminal octapeptide (OP) in the arcuate nucleus strongly reduces food intake. Up to now, the relevance of extrahypothalamic targets for endozepine signaling-mediated anorexia has been largely ignored. We focused our study on the dorsal vagal complex located in the caudal brainstem. This structure is strongly involved in the homeostatic control of food intake and comprises structural similarities with the hypothalamus. In particular, a circumventricular organ, the area postrema (AP) and a tanycyte-like cells forming barrier between the AP and the adjacent nucleus tractus solitarius (NTS) are present. We show here that DBI is highly expressed by ependymocytes lining the fourth ventricle, tanycytes-like cells, as well as by proteoplasmic astrocytes located in the vicinity of AP/NTS interface. ODN staining observed at the electron microscopic level reveals that ODN-expressing tanycyte-like cells and protoplasmic astrocytes are sometimes found in close apposition to neuronal elements such as dendritic profiles or axon terminals. Intracerebroventricular injection of ODN or OP in the fourth ventricle triggers c-Fos activation in the dorsal vagal complex and strongly reduces food intake. We also show that, similarly to leptin, ODN inhibits the swallowing reflex when microinjected into the swallowing pattern generator located in the NTS. In conclusion, we hypothesized that ODN expressing cells located at the AP/NTS interface could release ODN and modify excitability of NTS neurocircuitries involved in food intake control. [ABSTRACT FROM AUTHOR]

Objective The study was designed to determine metformin effects on meal pattern, gastric emptying, energy expenditure, and to identify metformin-sensitive neurons and their phenotype. Methods This study was performed on C57BL/6J and obese/diabetic (db/db) mice. Metformin (300 mg/kg) was administered by oral gavage. Food intake, meal pattern, oxygen consumption ( VO2), and carbon dioxide production ( VCO2) were obtained using an Oxylet Physiocage System. Gastric emptying assay and real-time RT-PCR from dorsal vagal complex extracts were also performed. C-Fos expression was used as a marker of neuronal activation. Phenotypic characterization of activated neurons was performed using either proopiomelanocortin (POMC)-Tau-Topaz GFP transgenic mice or NUCB2/nesfatin-1 and tyrosine hydroxylase (TH) labeling. Results Acute per os metformin treatment slowed down gastric emptying, reduced meal size, but not meal number in a leptin-independent manner, and transiently decreased energy expenditure in a leptin-dependent manner. Metformin specifically activated central circuitry within the brainstem, independently of vagal afferents. Finally, while POMC neurons seemed sparsely activated, we report that a high proportion of the c-Fos positive cells were nesfatinergic neurons, some of which coexpressing TH. Conclusions Altogether, these results show that metformin modifies satiation by activating brainstem circuitry and suggest that NUCB2/nesfatin-1 could be involved in this metformin effect. [ABSTRACT FROM AUTHOR]

Physiological regulations of energy balance and body weight imply highly adaptive mechanisms which match caloric intake to caloric expenditure. In the central nervous system, the regulation of appetite relies on complex neurocircuitry which disturbance may alter energy balance and result in anorexia or obesity. Deoxynivalenol (DON), a trichothecene, is one of the most abundant mycotoxins found on contaminated cereals and its stability during processing and cooking explains its widespread presence in human food. DON has been implicated in acute and chronic illnesses in both humans and farm animals including weight loss. Here, we provide the first demonstration that DON reduced feeding behavior and modified satiation and satiety by interfering with central neuronal networks dedicated to food intake regulation. Moreover, our results strongly suggest that during intoxication, DON reaches the brain where it modifies anorexigenic balance. In view of the widespread human exposure to DON, the present results may lead to reconsider the potential consequences of chronic DON consumption on human eating disorders. [ABSTRACT FROM AUTHOR]

Abstract: Neurotrophins, and in particular BDNF, play important roles in proliferation, differentiation and survival of neurons during development, as well as in the synaptic activity and plasticity in many groups of mature neurons. Several lines of evidence suggest that BDNF and its high affinity receptor TrkB contribute to food intake and body weight control. In rodents, pharmacological treatments with BDNF induce reduction in food intake, whereas genetic models with an altered BDNF/TrkB signalling display hyperphagia and obesity. Genetic studies in humans have shown that mutations in the BDNF or TrkB genes may account for certain types of obesity or other forms of eating disorders. Since circulating levels of BDNF correlate with eating disorders in humans and peripheral BDNF treatments reduce hyperphagia and hyperglycaemia in obese diabetic rodents, an endocrine role of BDNF appears plausible and requires further investigation. A central anorectic action of BDNF has also been documented, with a primary focus on the hypothalamus and a more recent highlight on the brainstem integrator of energy homeostasis, the dorsal vagal complex. In this review, we will briefly present neurotrophins and their receptors and focus on experimental evidence which point out BDNF as a signalling component of food intake regulation, with a particular emphasis on the localization of the central anorectic action of BDNF. [Copyright &y& Elsevier]

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level. [ABSTRACT FROM AUTHOR]

We have determined the three-dimensional structure of the potassium channel inhibitor HsTX1, using nuclear magnetic resonance and molecular modeling. This protein belongs to the scorpion short toxin family, which essentially contains potassium channel blockers of 29 to 39 amino acids and three disulfide bridges. It is highly active on voltage-gated Kv1.3 potassium channels. Furthermore, it has the particularity to possess a fourth disulfide bridge. We show that HsTX1 has a fold similar to that of the three-disulfide-bridged toxins and conserves the hydrophobic core found in the scorpion short toxins. Thus, the fourth bridge has no influence on the global conformation of HsTX1. Most residues spatially analogous to those interacting with voltage-gated potassium channels in the three-disulfide-bridged toxins are conserved in HsTX1. Thus, we propose that Tyr21, Lys23, Met25, and Asn26 are involved in the biological activity of HsTX1. As an additional positively charged residue is always spatially close to the aromatic residue in toxins blocking the voltage-gated potassium channels, and as previous mutagenesis experiments have shown the critical role played by the C-terminus in HsTX1, we suggest that Arg33 is also important for the activity of the four disulfide-bridged toxin. Docking calculations confirm that, if Lys23 and Met25 interact with the GYGDMH motif of Kv1.3, Arg33 can contact Asp386 and, thus, play the role of the additional positively charged residue of the toxin functional site. This original configuration of the binding site of HsTX1 for Kv1.3, if confirmed experimentally, offers new structural possibilities for the construction of a molecule blocking the voltage-gated potassium channels. [ABSTRACT FROM AUTHOR]

Reports that three novel toxins belonging to the scorpion K+ channel-inhibitor family were purified to homogeneity from the venom of the Chinese scorpion Buthus martensi. Process of purification of the toxins; Physicochemical characterization of the toxins; Effects of Bm toxins on voltage-gated K+ channels; Effects of Bm toxins on BKCa channels.

Investigates the mechanism of action of 2-(1non-8enyl)-5-(1non-8enyl)pyrrolidine (Pyr9), a synthetic derivative of 2,5-dialkylpyrrolidines, in vitro on preparations of the ventral nerve cord of the crayfish Procambarus clarkii. Study methodology; Results of study; Indication that Pyr9 blocks spike conduction without affecting the resting potential; Discussion of the results.

Four peptidyl inhibitors of the small-conductance Ca2+-activated K+ channels (SKca) have been isolated from the venom of the Chinese scorpion Buthus martensi. These peptides were identified by screening C18 HPLC fractions of the crude venom by means of mass analysis by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry, and toxicological tests in mice. Edman degradation analysis of the purified peptides showed sequences of 28–31 amino acids including 6 cysteine residues. Three of the sequences were similar to the P01 peptides from Androctonus scorpions, showing 76% sequence similarity for the most closely related, named BmP01. and 46% for the other two, named BmP02 and BmP03. Like the P01 peptides, these molecules showed a low toxic activity in mice after intracerebro-ventricular injection, and competed (K0.5 > 1 μM) with iodinated apamin for binding to its receptor site from rat brain, which has been proved to be the SKca channels. The fourth toxin was structurally related to the P05/leiurotixin I toxin family, with 90% similarity, and was named BmP05. This toxin exhibited a high toxic activity with lethal effects in mice. Due to its small representation in the venom [less than 0.01% (by mass)], its biological properties have been assessed on the synthetic analogue of BmP05. which was assembled on a solid phase by means of Fmoc methodology. The synthetic peptide was physicochemically identical to the natural peptide, as shown by comparison of their molecular masses and amino acid compositions, and by their coelution after coinjection on capillary electrophoresis. These results confirmed the primary structure of BmP05 including an amidated C-terminus. Similarly to natural BmP05, synthetic BmP05 produced toxic and lethal effects after intracerebroventricular injection in mice (LD50 = 37 rig). and was able to compete with iodinated apamin for binding to its receptor in rat brain (K0.5 = 20 pM). [ABSTRACT FROM AUTHOR]

The European Commission may reject the request by a plaintiff in a national follow-on proceeding to access the documents discovered in the context of an EU cartel proceeding.The Court of Justice decided that the European Commission may reject the request by a plaintiff in a national follow-on proceeding to access the documents discovered in the context of an EU cartel proceeding. For the Court of the Justice, there is a general presumption that such an access may jeopardize the interests protected by the regulations implementing the EU antitrust rules. This judgment limits the access to DG COMP's documents defined under CDC v Commission (T-437/08, CDC v Commission, 15 December 2011) and may introduce another standard compared with the test defined under Pfleiderer to access documents detained by national competition authorities (C-360/09, Pfleiderer, 14 June 2011). In these cases, the Court of Justice decided that a plaintiff in a follow-on action could, under the supervision of the national court in charge of the case, access the documents of a national competition authority, including those submitted under the leniency proceeding, if they are necessary to demonstrate the fault and the scope of the damage suffered. [ABSTRACT FROM PUBLISHER]