Journal Article

GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner

Denoyelle, Severine, Perello, Mario, Tolle, Virginie, Giovambattista, Andrés, Schiöth, Helgi B., Fehrentz, Jean-Alain, De Francesco, Pablo N., Cabral, Agustina, Cantel, Sonia, Fernandez, Gimena, Reynaldo, Mirta, Zubiría, Guillermina, Castrogiovanni, Daniel, Uriarte, Maia

2022

Overview

Objective Prolonged fasting is a major challenge for living organisms. An appropriate metabolic response to food deprivation requires the activation of the corticotropin-releasing factor-producing neurons of the hypothalamic paraventricular nucleus (PVH CRF neurons), which are a part of the hypothalamic–pituitary–adrenal axis (HPA), as well as the growth hormone secretagogue receptor (GHSR) signaling, whose activity is up- or down-regulated, respectively, by the hormones ghrelin and the liver-expressed antimicrobial peptide 2 (LEAP2). Since ghrelin treatment potently up-regulates the HPA axis, we studied the role of GHSR in mediating food deprivation-induced activation of the PVH CRF neurons in mice. Methods We estimated the activation of the PVH CRF neurons, using immuno-staining against CRF and the marker of neuronal activation c-Fos in brain sections, and assessed plasma levels of corticosterone and glucose in different pharmacologically or genetically manipulated mouse models exposed, or not, to a 2-day food deprivation protocol. In particular, we investigated ad libitum fed or food-deprived male mice that: (1) lacked GHSR gene expression, (2) had genetic deletion of the ghrelin gene, (3) displayed neurotoxic ablation of the hypothalamic arcuate nucleus, (4) were centrally treated with an anti-ghrelin antibody to block central ghrelin action, (5) were centrally treated with a GHSR ligand that blocks ghrelin-evoked and constitutive GHSR activities, or (6) received a continuous systemic infusion of LEAP2(1–12). Results We found that food deprivation results in the activation of the PVH CRF neurons and in a rise of the ghrelin/LEAP2 molar ratio. Food deprivation-induced activation of PVH CRF neurons required the presence and the signaling of GHSR at hypothalamic level, but not of ghrelin. Finally, we found that preventing the food deprivation-induced fall of LEAP2 reverses the activation of the PVH CRF neurons in food-deprived mice, although it has no effect on body weight or blood glucose. Conclusion Food deprivation-induced activation of the PVH CRF neurons involves ghrelin-independent actions of GHSR at hypothalamic level and requires a decrease of plasma LEAP2 levels. We propose that the up-regulation of the actions of GHSR associated to the fall of plasma LEAP2 level are physiologically relevant neuroendocrine signals during a prolonged fasting. Graphical abstract

• Publisher: Springer International Publishing,Springer Nature B.V,Springer Verlag
• Subject: Ablation / ad libitum feeding / Animal models / Animals / Antibodies / Antiinfectives and antibacterials / Antimicrobial Cationic Peptides / Antimicrobial Cationic Peptides - metabolism / Antimicrobial peptides / Arcuate nucleus / biochemical pathways / Biochemistry / Biochemistry, Molecular Biology / Biomedical and Life Sciences / Biomedicine / blood glucose / Body weight / brain / c-Fos protein / Cell Biology / Chemical Sciences / Constitutive GHSR activity / Corticosterone / Corticotropin-Releasing Hormone / Corticotropin-Releasing Hormone - metabolism / Corticotropin-Releasing Hormone - pharmacology / CRH neurons / Deprivation / Dietary restrictions / Eating / Fasting / Food / Food Deprivation / Gene deletion / Gene expression / genes / Ghrelin / Ghrelin - metabolism / Ghrelin - pharmacology / ghrelin receptors / Glucose / Growth hormones / Hormones / Hypothalamic-pituitary-adrenal axis / Hypothalamo-Hypophyseal System / Hypothalamo-Hypophyseal System - metabolism / Hypothalamus / Life Sciences / ligands / Male / males / Medicinal Chemistry / Metabolic response / Mice / Neurons / Neurons - metabolism / Neurotoxicity / Original / Original Article / Paraventricular Hypothalamic Nucleus / Paraventricular Hypothalamic Nucleus - cytology / Paraventricular Hypothalamic Nucleus - metabolism / Paraventricular nucleus / Pituitary / Pituitary-Adrenal System / Pituitary-Adrenal System - metabolism / Plasma levels / Receptors, Ghrelin / Receptors, Ghrelin - genetics / Receptors, Ghrelin - metabolism / Signaling