Constitutively active microglial populations limit anorexia induced by the food contaminant deoxynivalenol.

Microglia are involved in neuroinflammatory processes during diverse pathophysiological conditions. To date, the possible contribution of these cells to deoxynivalenol (DON)-induced brain inflammation and anorexia has not yet been evaluated. DON, one of the most abundant trichothecenes found in cereals, has been implicated in mycotoxicosis in both humans and farm animals. DON-induced toxicity is characterized by reduced food intake, weight gain, and immunological effects. We previously showed that exposure to DON induces an inflammatory response within the hypothalamus and dorsal vagal complex (DVC) which contributes to DON-induced anorexia. Here, in response to anorectic DON doses, we reported microglial activation within two circumventricular organs (CVOs), the area postrema (AP) and median eminence (ME) located in the DVC and the hypothalamus, respectively. Interestingly, this microglial activation was observed while DON-induced anorexia was ongoing (i.e., 3 and 6 h after DON administration). Next, we took advantage of pharmacological microglia deletion using PLX3397, a colony-stimulating factor 1 receptor (CSF1R)-inhibitor. Surprisingly, microglia-depleted mice exhibited an increased sensitivity to DON since non-anorectic DON doses reduced food intake in PLX3397-treated mice. Moreover, low DON doses induced c-Fos expression within feeding behavior-associated structures in PLX3397-treated mice but not in control mice. In parallel, we have highlighted heterogeneity in the phenotype of microglial cells present in and around the AP and ME of control animals. In these areas, microglial subpopulations expressed IBA1, TMEM119, CD11b and CD68 to varying degrees. In addition, a CD68 positive subpopulation showed, under resting conditions, a noticeable phagocytotic/endocytotic activity. We observed that DON strongly reduced CD68 in the hypothalamus and DVC. Finally, inactivation of constitutively active microglia by intraperitoneal administration of minocycline resulted in anorexia with a DON dose ineffective in control mice. Taken together, these results strongly suggest that various populations of microglial cells residing in and around the CVOs are maintained in a functionally active state even under physiological conditions. We propose that these microglial cell populations are attempting to protect the brain parenchyma from hazardous molecules coming from the blood. This study could contribute to a better understanding of how microglia respond to environmental contaminants.

Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake.

The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the awareness of energy homeostasis control remains an important worldwide issue. The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal networks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional, humoral and nervous information from the periphery. The glial cells' contribution to these processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally, we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.

The food contaminant deoxynivalenol provokes metabolic impairments resulting in non-alcoholic fatty liver (NAFL) in mice.

The ribotoxin deoxynivalenol (DON) is a trichothecene found on cereals responsible for mycotoxicosis in both humans and farm animals. DON toxicity is characterized by reduced food intake, diminished nutritional efficiency and immunologic effects. The present study was designed to further characterize the alterations in energy metabolism induced by DON intoxication. We demonstrated that acute DON intoxication triggered liver steatosis associated with an altered expression of genes related to lipids oxidation, lipogenesis and lipolysis. This steatosis was concomitant to anorexia, hypoglycemia and a paradoxical transient insulin release. DON treatment resulted also in stimulation of central autonomic network regulating sympathetic outflow and adrenaline and glucocorticoids secretion. Furthermore, an increased expression of genes linked to inflammation and reticulum endoplasmic stress was observed in the liver of DON-treated mice. Finally, we propose that lipids mobilization from adipose tissues (AT) induced by DON intoxication drives hepatic steatosis since (1) genes encoding lipolytic enzymes were up-regulated in AT and (2) plasma concentration of triglycerides (TGs) and non-esterified fatty acids were increased during DON intoxication. Altogether, these data demonstrate that DON induced hormonal and metabolic dysregulations associated with a spectrum of hepatic abnormalities, evocative of a non-alcoholic fatty liver disease.

Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin.

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.

Interaction between nesfatin-1 and oxytocin in the modulation of the swallowing reflex.

Nesfatin-1, an 82-amino acid peptide encoded by the secreted precursor nucleobinin-2 (NUCB2), exerts potent anorexigenic action independently of leptin signaling. This propensity has propelled this peptide and its analogues as potential anti-obesity drug candidates. However, a more extensive comprehension of its biological actions is needed prior to envisaging its potential use in the treatment of metabolic diseases. Swallowing is an essential motor component of ingestive behavior, which induces the propulsion of the alimentary bolus from the mouth to the esophagus. The dorsal swallowing group (DSG) which constitutes a part of the central pattern generator of swallowing (SwCPG) is located within the solitary tract nucleus (STN), a region reported to contain nesfatin-1/NUCB2 expressing neurons. In this context, we investigate here the possible effects of nesfatin-1 on swallowing discharge. Nesfatin-1 dose-dependently inhibited swallowing reflex and activated neurons located in the DSG region. In addition, we provide evidences that strongly suggest that this nesfatin-1 inhibitory effect involved an oxytocinergic relay. Indeed, oxytocin (OT) injection at the brainstem level inhibited swallowing reflex and OT receptor antagonist prevented nesfatin-1 inhibitory action. Altogether, these data constitute the first demonstration that nesfatin-1 modulates swallowing reflex by acting at the brainstem level via an oxytocinergic relay.

Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity.

Chronic low-grade inflammation is known to be linked to obesity, and to occur in the early stages of the disease. This mechanism is complex and involves numerous organs, cells, and cytokines. In this context, inflammation of white adipose tissue seems to play a key role in the development of obesity. Because of its properties, prostaglandin E2 (PGE2), an emblematic inflammatory mediator, has been proposed as an actor linking inflammation and obesity. Indeed, PGE2 is involved in mechanisms that are dysregulated in obesity such as lipolysis and adipogenesis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which specifically catalyzes the final step of PGE2 biosynthesis. Interestingly, mPGES-1 invalidation dramatically alters the production of PGE2 during inflammation. In the present work, we sought to determine whether mPGES-1 could contribute to inflammation associated with obesity. To this end, we analyzed the energy metabolism of mPGES-1 deficient mice (mPGES-1-/-) and littermate controls, fed with a high-fat diet. Our data showed that mPGES-1-/- mice exhibited resistance to diet-induced obesity when compared to wild-type littermates. mPGES-1-/- mice fed with a high-fat diet, showed a lower body weight gain and a reduced adiposity, which were accompanied by a decrease in adipose tissues inflammation. We also observed an increase in energy expenditures in mPGES-1-/- mice fed with a high-fat diet without any changes in activity and browning process. Altogether, these data suggest that mPGES-1 inhibition may prevent diet-induced obesity.

Glial Endozepines Inhibit Feeding-Related Autonomic Functions by Acting at the Brainstem Level.

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.

Dysregulation of energy balance by trichothecene mycotoxins: Mechanisms and prospects.

Trichothecenes are toxic metabolites produced by fungi that constitute a worldwide hazard for agricultural production and both animal and human health. More than 40 countries have introduced regulations or guidelines for food and feed contamination levels of the most prevalent trichothecene, deoxynivalenol (DON), on the basis of its ability to cause growth suppression. With the development of analytical tools, evaluation of food contamination and exposure revealed that a significant proportion of the human population is chronically exposed to DON doses exceeding the provisional maximum tolerable daily dose. Accordingly, a better understanding of trichothecene impact on health is needed. Upon exposure to low or moderate doses, DON and other trichothecenes induce anorexia, vomiting and reduced weight gain. Several recent studies have addressed the mechanisms by which trichothecenes induce these symptoms and revealed a multifaceted action targeting gut, liver and brain and causing dysregulation in neuroendocrine signaling, immune responses, growth hormone axis, and central neurocircuitries involved in energy homeostasis. Newly identified trichothecene toxicosis biomarkers are just beginning to be exploited and already open up new questions on the potential harmful effects of chronic exposure to DON at apparently asymptomatic very low levels. This review summarizes our current understanding of the effects of DON and other trichothecenes on food intake and weight growth.

Leptin is required for hypothalamic regulation of miRNAs targeting POMC 3'UTR.

The central nervous system (CNS) monitors modifications in metabolic parameters or hormone levels and elicits adaptive responses such as food intake regulation. Particularly, within the hypothalamus, leptin modulates the activity of pro-opiomelanocortin (POMC) neurons which are critical regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the POMC gene causes hyperphagia and obesity. MicroRNAs (miRNAs) are short noncoding RNA molecules that post-transcriptionally repress the expression of genes by binding to 3'-untranslated regions (3'UTR) of the target mRNAs. However, little is known regarding the role of miRNAs that target POMC 3'UTR in the central control energy homeostasis. Particularly, their interaction with the leptin signaling pathway remain unclear. First, we used common prediction programs to search for potential miRNAs target sites on 3'UTR of POMC mRNA. This screening identified a set of conserved miRNAs seed sequences for mir-383, mir-384-3p, and mir-488. We observed that mir-383, mir-384-3p, and mir-488 are up-regulated in the hypothalamus of leptin deficient ob/ob mice. In accordance with these observations, we also showed that mir-383, mir-384-3p, and mir-488 were increased in db/db mice that exhibit a non-functional leptin receptor. The intraperitoneal injection of leptin down-regulated the expression of these miRNAs of interest in the hypothalamus of ob/ob mice showing the involvement of leptin in the expression of mir-383, mir-384-3p, and mir-488. Finally, the evaluation of responsivity to intracerebroventricular administration of leptin exhibited that a chronic treatment with leptin decreased mir-488 expression in hypothalamus of C57BL/6 mice. In summary, these results suggest that leptin modulates the expression of miRNAs that target POMC mRNA in hypothalamus.

The food born mycotoxin deoxynivalenol induces low-grade inflammation in mice in the absence of observed-adverse effects.

SCOPE: Deoxynivalenol (DON) is the most common fungi toxin contaminating cereals and cereal-derived products. High consumption of DON is implicated in mycotoxicoses and causes a set of symptoms including diarrhea, vomiting, reduced weight gain or immunologic effects. However, such clinical intoxications are rare in humans, who are most frequently, exposed to low DON doses without developing acute symptoms. The adverse effect of chronically consumed low DON doses can not be totally excluded. Using a mouse model, we evaluated the impact on inflammatory status of subchronic administration of DON given at doses comparable to the daily human consumption. METHODS AND RESULTS: The inflammatory status was evaluated in mice receiving 1, 2.5 or 25µg/kg bw/day DON during a 10 or 30 days period. The systemic interleukin-1 beta (IL-1ß) concentrations were evaluated by Elisa and inflammatory biomarker mRNA expressions were quantified by qPCR within brain structures and peripheral organs. While DON intake failed to modify physiological markers, we observed a systemic IL-1ß increase and a modulation of pro-inflammatory gene expression in brain structures, liver, duodenum and adipose tissue. CONCLUSION: We bring here the first evidence that subchronic DON intake, at doses that match daily human intake, induces, in a murine model, a central and peripheral low grade inflammation.

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons.

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.

Modification of energy balance induced by the food contaminant T-2 toxin: a multimodal gut-to-brain connection.

T-2 toxin is one of the most toxic Fusarium-derived trichothecenes found on cereals and constitutes a widespread contaminant of agricultural commodities as well as commercial foods. Low doses toxicity is characterized by reduced weight gain. To date, the mechanisms by which this mycotoxin profoundly modifies feeding behavior remain poorly understood and more broadly the effects of T-2 toxin on the central nervous system (CNS) have received limited attention. Through an extensive characterization of sickness-like behavior induced by T-2 toxin, we showed that its per os (p.o.) administration affects not only feeding behavior but also energy expenditure, glycaemia, body temperature and locomotor activity. Using c-Fos expression mapping, we identified the neuronal structures activated in response to T-2 toxin and observed that the pattern of neuronal populations activated by this toxin resembled that induced by inflammatory signals. Interestingly, part of neuronal pathways activated by the toxin were NUCB-2/nesfatin-1 expressing neurons. Unexpectedly, while T-2 toxin induced a strong peripheral inflammation, the brain exhibited limited inflammatory response at a time point when anorexia was ongoing. Unilateral vagotomy partly reduced T-2 toxin-induced brainstem neuronal activation. On the other hand, intracerebroventricular (icv) T-2 toxin injection resulted in a rapid (<1h) reduction in food intake. Thus, we hypothesized that T-2 toxin could signal to the brain through neuronal and/or humoral pathways. The present work provides the first demonstration that T-2 toxin modifies feeding behavior by interfering with central neuronal networks devoted to central energy balance. Our results, with a particular attention to peripheral inflammation, strongly suggest that inflammatory mediators partake in the T-2 toxin-induced anorexia and other symptoms. In view of the broad human and breeding animal exposure to T-2 toxin, this new mechanism may lead to reconsider the impact of the consumption of this toxin on human health.

The central question of type 2 diabetes.

Type 2 diabetes (T2D) represents a significant global epidemic with more than 285 million people affected worldwide. Regulating glycemia in T2D patients can be partially achieved with currently available treatment, but intensive research during the last decades have led to the discovery of modified compounds or new targets that could represent great hope for safe and effective treatment in the future. Among them, targets in the CNS that are known to control feeding and body weight have been also shown to exert glucoregulatory actions, and could be a key in the development of a new generation of drugs in the field of T2D. Such drugs would be of great interest since they can be used both in the treatment of diabetes and obesity. This patent review aims to establish an overview of recent patents disclosing new therapeutic opportunities targeting peripheral, as well as central targets for the treatment of T2D.

Gastric distension activates NUCB2/nesfatin-1-expressing neurons in the nucleus of the solitary tract.

Brainstem structures such as the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) are essential for the digestive function of the stomach. A large number of neurotransmitters including glutamate and gamma-aminobutyric acid (GABA) are involved in the central control of gastric functions. However, the neuropeptidergic systems implicated in this process remain undetermined. Nesfatin-1 was recently identified as a neuropeptide cleaved from the N-terminal part of NEFA/nucleobindin 2 precursor (NUCB2). Central administration of this neuropeptide inhibits food consumption and gastroduodenal motility in rodents. Interestingly, the NTS and the DMNX contain a dense population of NUCB2/nesfatin-1 cell bodies. These observations led us to investigate the possible involvement of NUCB2/nesfatin-1 neurons in the brainstem neuronal pathways that modulate gastric functions. We observed an activation of NTS NUCB2/nesfatinergic neurons after gastric distention in rats. In addition, we found that several NTS NUCB2/nesfatinergic neurons were GABAergic. Finally, when fluorogold was injected at the stomach level, many retrogradely labeled neurons were observed in the DMNX which were also positive for NUCB2/nesfatin-1. Taken together, these observations suggest for the first time that NUCB2/nesfatin-1 neurons of the NTS are sensitive to gastric distension and then may contribute to the satiety signal.

c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons.

Deoxynivalenol (DON), produced by the cereal-contaminating Fusarium fungi, is a major trichothecene responsible for mycotoxicoses in farm animals, including swine. The main effect of DON-intoxication is food intake reduction and the consequent body weight loss. The present study aimed to identify brain structures activated during DON intoxication in pigs. To this goal, we used c-Fos staining which constitutes a useful approach to identify activated neurons. We showed that per os administration of Fusarium graminearum extracts (containing the equivalent of 1mg DON per kg of body weight) induced an increase in c-Fos immunoreactivity in several central structures, including the ventrolateral medulla (VLM), dorsal vagal complex (DVC), paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus (Arc), supraoptic nucleus (SON) and amygdala (CeA). Moreover, we coupled c-Fos staining with phenotypic markers detection in order to specify the neuronal populations activated during DON intoxication. This phenotypic characterization revealed the activation of catecholaminergic but not of serotoninergic neurons in response to the toxin. In this context, we also paid a particular attention to NUCB2/nesfatin-1 positive cells, since nesfatin-1 is known to exert a satiety effect. We report here, for the first time in the pig brain, the presence of NUCB2/nesfatin-1 neurons in the VLM, DVC, PVN, Arc and SON, and their activation during DON intoxication. Taken together, these data show that DON stimulates the main structures involved in food intake in pigs and suggest that catecholaminergic and NUCB2/nesfatin-1 neurons could contribute in the anorexigenic effects of the mycotoxin.

Advances in deoxynivalenol toxicity mechanisms: the brain as a target.

Deoxynivalenol (DON), mainly produced by Fusarium fungi, and also commonly called vomitoxin, is a trichothecene mycotoxin. It is one of the most abundant trichothecenes which contaminate cereals consumed by farm animals and humans. The extent of cereal contamination is strongly associated with rainfall and moisture at the time of flowering and with grain storage conditions. DON consumption may result in intoxication, the severity of which is dose-dependent and may lead to different symptoms including anorexia, vomiting, reduced weight gain, neuroendocrine changes, immunological effects, diarrhea, leukocytosis, hemorrhage or circulatory shock. During the last two decades, many studies have described DON toxicity using diverse animal species as a model. While the action of the toxin on peripheral organs and tissues is well documented, data illustrating its effect on the brain are significantly less abundant. Yet, DON is known to affect the central nervous system. Recent studies have provided new evidence and detail regarding the action of the toxin on the brain. The purpose of the present review is to summarize critical studies illustrating this central action of the toxin and to suggest research perspectives in this field.

Properties of subependymal cerebrospinal fluid contacting neurones in the dorsal vagal complex of the mouse brainstem.

Cerebrospinal fluid (CSF) contacting neurones have been observed in various brain regions such as the hypothalamus, the dorsal nucleus of the raphe and around the central canal (cc) of the spinal cord but their functional role remains unclear. At the level of the spinal cord, subependymal cerebrospinal fluid contacting neurones (S-CSF-cNs) present a peculiar morphology with a soma close to the ependymal layer, a process projecting towards the cc and ending with a bud and a cilium. These neurones were recently shown to express polycystin kidney disease 2-like 1 (PKD2L1 or TRPP3) channels that are members of the polycystin subtype of the transient receptor potential (TRP) channel superfamily and that have been proposed as either chemo- or mechanoreceptors in several tissues. Using immunohistological techniques and whole-cell electrophysiological recordings in brain slices obtained from PKD2L1:EGFP transgenic adult mice, we looked for and determined the functional properties of S-CSF-cNs in the dorsal vagal complex (DVC), a hindbrain structure controlling autonomic functions such as blood pressure, energy balance and food intake. Here, we demonstrate that S-CSF-cNs received GABAergic and/or glycinergic synaptic entries and were also characterised by the presence of non-selective cationic channels of large conductance that could be detected even under whole-cell configuration. The channel activity was not affected by Psalmopoeus cambridgei toxin 1, a blocker of acid sensing ion channels (ASICs), but was blocked by amiloride and by a strong extracellular acidification. In contrast, extracellular alkalinisation and hypo-osmotic shocks increased channel activity. Based on these properties, we suggest that the single-channel activity recorded in medullar S-CSF-cNs is carried by PKD2L1 channels. Our study therefore reinforces the idea that PKD2L1 is a marker of S-CSF-cNs and points toward a role for S-CSF-cNs in the detection of circulating signals and of modifications in the extracellular environment.

The food-contaminant deoxynivalenol modifies eating by targeting anorexigenic neurocircuitry.

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.

An update in the management of obesity: the weight of CNS targets.

Obesity is one of the most important and disturbing global epidemic that affects humans, with more than 2 billion people overweight and 700 million obese predicted for 2015 by the World Health Organization. Obesity treatment represents then one of the most exciting challenges for the academic researchers and the pharmaceutical industry. But to date, this community failed to develop safe and effective treatments with a good risk/benefit profile. Indeed, most of the drugs previously used as anti-obesity agents have been withdrawn from the market for safety issues, and therapeutic options in form of a medication are currently very limited. This last decade however, new advances in our understanding of central pathways controlling food intake, body weight and energy homeostasis have led to the discovery of new molecular targets that could provide interesting options in the fight against obesity. This review aims to be an overview of the new patents exploiting the anorexigenic properties of the central catabolic pathways or aimed at blocking the orexigenic effects of the anabolic pathways, in the hope to develop new anti-obesity drugs.

Central inflammation and sickness-like behavior induced by the food contaminant deoxynivalenol: a PGE2-independent mechanism.

Deoxynivalenol (DON), one of the most abundant trichothecenes found on cereals, has been implicated in mycotoxicoses in both humans and farm animals. Low-dose toxicity is characterized by reduced weight gain, diminished nutritional efficiency, and immunologic effects. The levels and patterns of human food commodity contamination justify that DON consumption constitutes a public health issue. DON stability during processing and cooking explains its large presence in human food. We characterized here DON intoxication by showing that the toxin concomitantly affects feeding behavior, body temperature, and locomotor activity after both per os and central administration. Using c-Fos expression mapping, we identified the neuronal structures activated in response to DON and observed that the pattern of neuronal populations activated by the toxin resembled those induced by inflammatory signals. By real-time PCR, we report the first evidences for a DON-induced central inflammation, attested by the strong upregulation of interleukin-1ß, interleukin-6, tumor necrosis factor-α, cyclooxygenase-2, and microsomal prostaglandin synthase-1 (mPGES-1) messenger RNA. However, silencing prostaglandins E2 signaling pathways using mPGES-1 knockout mice, which are resistant to cytokine-induced sickness behavior, did not modify the responses to the toxin. These results reveal that, despite strong similarities, behavioral changes observed after DON intoxication differ from classical sickness behavior evoked by inflammatory cytokines.