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

FERNANDEZ, GIMENA; PABLO NICOLAS DE FRANCESCO; MAIA URIARTE DONATI; DANIEL CASTROGIOVANNI; ZUBIRIA, GUILLERMINA; CANTEL, SONIA; SEVERINE DENOYELLE; VIRGINIE TOLLE; HELGI B. SCHIÖTH; AGUSTINA CABRAL; MIRTA REYNALDO; GIOVAMBATTISTA, ANDRES; FEHRENTZ, JEAN-ALAIN; MARIO PERELLO

CELLULAR AND MOLECULAR LIFE SCIENCES

BIRKHAUSER VERLAG AG

Lugar: BASEL; Año: 2022

1420-682X

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 (PVHCRF 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 PVHCRF neurons in mice.Methods: We estimated the activation of the PVHCRF 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 PVHCRF neurons and in a rise of the ghrelin/LEAP2 molar ratio. Food deprivation-induced activation of PVHCRF 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 PVHCRF neurons in food-deprived mice, although it has no effect on body weight or blood glucose. Conclusions: Food deprivation-induced activation of the PVHCRF 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.