Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation

Author:

Fernandez Gimena1ORCID,De Francesco Pablo N1ORCID,Cornejo María P1ORCID,Cabral Agustina1ORCID,Aguggia Julieta P1ORCID,Duque Victor J2ORCID,Sayar Nilufer3ORCID,Cantel Sonia4ORCID,Burgos Juan I5ORCID,Fehrentz Jean-Alain4ORCID,Rorato Rodrigo2ORCID,Atasoy Deniz3ORCID,Mecawi André S2ORCID,Perello Mario16ORCID

Affiliation:

1. Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata] , La Plata, Buenos Aires 1900 , Argentina

2. Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP) , São Paulo, CEP: 04023-062 , Brazil

3. Department of Neuroscience and Pharmacology, Carver College of Medicine, Iowa Neuroscience Institute and Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa , Iowa City, IA 52242 , USA

4. Institut des Biomolécules Max Mousseron, University of Montpellier, CNRS, ENSCM , Montpellier cedex 5 34293 , France

5. Centro de Investigaciones Cardiovasculares “Dr. Horacio Eugenio Cingolani” (CONICET and National University of La Plata) , La Plata 1900, Buenos Aires , Argentina

6. Department of Surgical Sciences, Functional Pharmacology and Neuroscience, University of Uppsala , Uppsala 751 05 , Sweden

Abstract

Abstract The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus–independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic–pituitary–adrenal neuroendocrine axis.

Publisher

The Endocrine Society

Subject

Endocrinology

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