title: Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents.
abstract: Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function by acting on its receptor, GHSR (Growth Hormone Secretagogue Receptor). Recent evidence indicates that a key function of ghrelin is to signal stress to the brain. It has been suggested that one of the potential stress-related ghrelin targets is the CRF (Corticotropin-Releasing Factor)-producing neurons of the hypothalamic paraventricular nucleus, which secrete the CRF neuropeptide into the median eminence and activate the hypothalamic-pituitary-adrenal axis. However, the neural circuits that mediate the ghrelin-induced activation of this neuroendocrine axis are mostly uncharacterized. In the current study, we characterized in vivo the mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that peripheral or intra-cerebro-ventricular administration of ghrelin strongly activates c-fos--a marker of cellular activation--in CRF-producing neurons. Also, ghrelin activates CRF gene expression in the paraventricular nucleus of the hypothalamus and the hypothalamic-pituitary-adrenal axis at peripheral level. Ghrelin administration directly into the paraventricular nucleus of the hypothalamus also induces c-fos within the CRF-producing neurons and the hypothalamic-pituitary-adrenal axis, without any significant effect on the food intake. Interestingly, dual-label immunohistochemical analysis and ghrelin binding studies failed to show GHSR expression in CRF neurons. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons, albeit indirectly.
authors.affiliation: Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), La Plata, Buenos Aires, Argentina.
authors.forename: Agustina
authors.initials: A
authors.lastname: Cabral
authors.forename: Olga
authors.initials: O
authors.lastname: Suescun
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Zigman
authors.forename: Mario
authors.initials: M
authors.lastname: Perello
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054440:Receptors, Ghrelin / Q000378:metabolism
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D003346:Corticotropin-Releasing Hormone