Michel Dallaporta

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

•u2002 The brainstem is a major site of integration for autonomic information from neurones, blood and cerebrospinal fluid (CSF). Signals exchange from the CSF is limited by the ependymocytes forming the brain cavities. However neurones contacting the CSF (CSF‐cNs) are thought to integrate those signals. •u2002 Using immunohistochemical and electrophysiological approaches, we characterise in the brainstem, subependymal CSF‐cNs projecting a process ending in the central canal with a protrusion and expressing a ‘transient receptor potential’ (TRP) channel subtype suggested to act as chemo‐ or mechanoreceptors: the polycystin kidney disease 2‐like 1 channels (PKD2L1). •u2002 CSF‐cNs receive exclusively inhibitory synaptic inputs and express functional channels presenting all properties of PKD2L1: cationic non‐selective, large conductance and modulated by extracellular pH and osmolarity. •u2002 Because medullar CSF‐cNs are strategically positioned between CSF and neuronal parenchyma, we hypothesise that they could play a role in the regulation of homeostasis by integrating CSF signals.

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.

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.

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.

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.

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.

SCOPEnDeoxynivalenol (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.nnnMETHODS AND RESULTSnThe 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-1β) 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-1β increase and a modulation of pro-inflammatory gene expression in brain structures, liver, duodenum and adipose tissue.nnnCONCLUSIONnWe 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.

Towards the Management of Inflammation: Recent Developments of mPGES-1 Inhibitors

For decades, the struggle against inflammation and related disorders has constituted an important field in medical practice, with strategies mainly aimed at inhibiting compounds produced through the arachidonic acid pathway. Thus, specific COX-2 inhibitors or coxibs, were recently designed, that play an increasing but controversial role in reducing inflammatory phenomenon. Lately, several patents have been generated which target the specific inhibition of the microsomal Prostanglandin E synthase-1 (mPGES-1). This enzyme, which was cloned and characterized at the end of the nineties, catalyzes under inflammatory stimuli the last step of PGE2 synthesis. A corpus of data is now available illustrating the pivotal role played by this enzyme in numerous symptoms linked to inflammation such as fever, anorexia or pain. The present review highlights the current state of knowledge of the involvement of mPGES-1 in sickness behaviour and in other inflammation-related disorders and summarizes the recent patents related to mPGES-1 and its specific inhibition.

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.