Control of food intake : Neurobiological aspects

La prise alimentaire, comportement vital pour la survie, est soumise à une intense régulation de la part du cerveau, afin de maintenir l’homéostasie énergétique. Les réseaux neuronaux, localisés dans les noyaux hypothalamiques et dans le complexe vagal dorsal du bulbe rachidien, jouent un rôle crucial dans l’intégration des signaux de satiété et d’adiposité. Contrairement à la conception classique du modèle hiérarchisé où l’hypothalamus joue le rôle majeur, les résultats actuels sont en faveur d’un modèle distributif. Il est intéressant de noter que la réorganisation des réseaux neuronaux et la neurogenèse sont impliquées dans la régulation de la prise alimentaire et du poids corporel , ce qui suggère que l’étude de la neuroplasticité pourrait ouvrir des pistes originales pour la compréhension des désordres de la balance énergétique tels que l’obésité.La prise alimentaire, comportement vital pour la survie, est soumise à une intense régulation de la part du cerveau, afin de maintenir l'homéostasie énergétique. Les réseaux neuronaux, localisés dans les noyaux hypothalamiques et dans le complexe vagal dorsal du bulbe rachidien, jouent un rôle crucial dans l'intégration des signaux de satiété et d'adiposité. Contrairement à la conception classique du modèle hiérarchisé où l'hypothalamus joue le rôle majeur, les résultats actuels sont en faveur d'un modèle distributif. Il est intéressant de noter que la réorganisation des réseaux neuronaux et la neurogenèse sont impliquées dans la régulation de la prise alimentaire et du poids corporel, ce qui suggère que l'étude de la neuroplasticité pourrait ouvrir des pistes originales pour la compréhension des désordres de la balance énergétique tels que l'obésité

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

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

International audienceThe 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

Implication du Brain-Derived Neurotrophic Factor (BDNF) au niveau du Complexe Vagal Dorsal (CVD) dans le contrôle de la prise alimentaire

Le BDNF a été impliqué en tant que facteur anorexigène dans la régulation centrale de la prise alimentaire. Dans le présent travail, nous identifions le CVD comme un site clef où le BDNF exerce son action anorexigène, en aval de la voie de signalisation mélanocortinergique. Chez le rat adulte, nous montrons que l application de BDNF exogène au niveau du CVD entraîne une anorexie et une perte de poids corporel, tandis que le taux tissulaire du BDNF endogène dans le CVD est modulé de façon cohérente avec un rôle anorexigène, au cours du nycthémère, en fonction du statut nutritionnel, ou après traitements par les hormones leptine, CCK et ghréline. De plus, l application d agonistes ou d antagonistes des récepteurs mélanocortinergiques de type 3/4 (MC3/4R) dans le 4ème ventricule induit respectivement une augmentation et une diminution du contenu en protéine BDNF du CVD, tandis que les effets orexigènes de l antagoniste MC3/4R sont bloqués par un co-traitement au BDNF exogène.AIX-MARSEILLE3-BU Sc.St Jérô (130552102) / SudocSudocFranceF

Alpha-Galacto-Oligosaccharides at Low Dose Improve Liver Steatosis in a High-Fat Diet Mouse Model

Non-Alcoholic Fatty Liver Disease (NAFLD) is the major liver disease worldwide and is linked to the development of metabolic syndrome and obesity. As alpha-galacto-oligosaccharides (α-GOS) from legumes have been shown to reduce body weight and hyperphagia in overweight adults, it was hypothesized that they would exert benefits on the development of metabolic syndrome and associated NAFLD in a rodent model. C57Bl/6J mice were fed a high-fat diet until they developed metabolic syndrome and were then orally treated either with α-GOS at a physiological dose (2.2 g/kg BW/d) or the vehicle over 7 weeks. α-GOS induced a reduction in food intake, but without affecting body weight during the first week of treatment, when compared to the vehicle. Fasting glycaemia was improved after 4 weeks of treatment with α-GOS, whereas insulin sensitivity (assessed with HOMA-IR) was unaffected at the end of the experiment. Plasma non-esterified fatty acids, low-density lipoprotein (LDL) and total cholesterol were lowered by α-GOS while high-density lipoprotein (HDL) and triglycerides levels remained unaffected. α-GOS markedly improved liver steatosis as well as free fatty acid and triglyceride accumulation in the liver. α-GOS improved plasma lipids and prevented NAFLD development through mechanisms which are independent of body weight management and glycemic control

Role of BDNF in the dorsal vagal complex of the Wistar rat and its implication in the swallowing reflex

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Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control.

International audienceIt has been shown that the neurotropin brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin-related kinase receptor type B (TrkB), contribute to the central control of food intake. BDNF has previously been implicated as a probable downstream effector of melanocortinergic signaling within the ventromedial hypothalamus, and we have shown its implication as an anorexigenic factor within the brainstem autonomic integrator of food intake control, namely the dorsal vagal complex (DVC). In the brainstem, the melanocortinergic signaling pathway is known to integrate phasic responses to satiety signals, such as cholecystokinin. In this study, we explored the interactions between melanocortin and BDNF/TrkB signaling within the DVC. First, we tested the effect of a local pharmacological activation or inhibition of melanocortin receptors type 3/4 (MC3/4R) on BDNF protein content in the DVC of adult rats. We showed that fourth intracerebroventricular delivery of MC3/4R agonist and antagonist increased and decreased the BDNF protein content within the DVC, respectively. Second, we showed that the orexigenic effect of a selective MC4R antagonist delivered fourth-icv can be blocked by a coadministration of BDNF. We also tested the causal role of BDNF/TrkB signaling in the anorexigenic effect of melanocortinergic signaling by using a recently developed analog-sensitive kinase allele murine model (TrkB(F616A) mice) and showed that the pharmacological blockade of TrkB abolished the anorexigenic effect of a selective MC4R agonist and of cholecystokinin. Our results provide strong evidence for a role of BDNF as a downstream effector of melanocortinergic signaling pathway within the DVC

BDNF-TrkB signaling interacts with the GABAergic system to inhibit rhythmic swallowing in the rat

International audienceBrain-derived neurotrophic factor (BDNF) acts as an anorexigenic factor in the dorsal vagal complex (DVC) of the adult rat brain stem. The DVC contains the premotoneurons controlling swallowing, a motor component of feeding behavior. Although rats with transected midbrain do not seek out food, they are able to swallow and to ingest food. Because BDNF and tropomyosin-related kinase B (TrkB) receptors are expressed in the DVC, this study hypothesized that BDNF could modify the activity of premotoneurons involved in swallowing. Repetitive electrical stimulation of the superior laryngeal nerve (SLN) induces rhythmic swallowing that can be recorded with electromyographic electrodes inserted in sublingual muscles. We show that a microinjection of BDNF in the swallowing network induced a rapid, transient, and dose-dependant inhibition of rhythmic swallowing. This BDNF effect appeared to be mediated via TrkB activation, since it no longer occurred when TrkB receptors were antagonized by K-252a. Interestingly, swallowing was inhibited when subthreshold doses of BDNF and GABA were coinjected, suggesting a synergistic interaction between these two signaling substances. Moreover, BDNF no longer had an inhibitory effect on swallowing when coinjected with bicuculline, a GABAA receptor antagonist. This blockade of BDNF inhibitory effect on swallowing was reversible, since it reappeared when BDNF was injected 15 min after bicuculline. Finally, we show that stimulation of SLN induced a decrease in BDNF protein within the DVC. Together, our results strongly suggest that BDNF inhibits swallowing via modulation of the GABAergic signaling within the central pattern generator of swallowin