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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

Centre de Recherche de Neurobiologie et Neurophysiologie de Marseille, Département de Physiologie Neurovégétative, Université Paul Cézanne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6231, Institut National de la Recherche Agronomique Unité sous contrat 2027, Faculté des Sciences et Techniques de Saint-Jérôme, F-13397 Marseille Cedex 20, France

Address all correspondence and requests for reprints to: Bruno Lebrun, Centre de Recherche de Neurobiologie et Neurophysiologie de Marseille, CRN2M, Département de Physiologie Neurovégétative, Université Paul Cézanne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6231, Institut National de la Recherche Agronomique Unité sous contrat 2027; Faculté des Sciences et Techniques St Jérôme, Avenue Escadrille Normandie Niémen, F-13397 Marseille cedex 20, BP 351-352 France. E-mail: bruno.lebrun{at}univ-cezanne.fr.

It 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.

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