title: Modification of energy balance induced by the food contaminant T-2 toxin: a multimodal gut-to-brain connection.
abstract: 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.
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gaigé
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Djelloul
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France; INRA U1189, Département AlimH, 63122 St Genés Champenelle, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tardivel
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France.
authors.forename: Coraline
authors.initials: C
authors.lastname: Airault
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France; INRA U1189, Département AlimH, 63122 St Genés Champenelle, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Félix
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France.
authors.forename: André
authors.initials: A
authors.lastname: Jean
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lebrun
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France. Electronic address: j-d.troadec@univ-amu.fr.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Troadec
authors.affiliation: EA 4674, Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, FST St Jérôme. Aix-Marseille Université, Avenue Escadrille Normandie-Niemen, 13013 Marseille, France. Electronic address: michel.dallaporta@univ-amu.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Dallaporta
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002151:Calorimetry; D004734:Energy Metabolism / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D055809:Illness Behavior / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress; D013154:Spleen / Q000378:metabolism; D013605:T-2 Toxin / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D013605:T-2 Toxin
keywords: Anorexia; Inflammation; ROS; Sickness behavior; Trichothecenes; c-Fos