Ghrelin-induced Food Intake, but not GH Secretion, Requires the Expression of the GH Receptor in the Brain of Male Mice

Author(s)

Wasinski, Frederick ^[1] ; Barrile, Franco ^[2] ; Pedroso, Joao A. B. ^[1] ; Quaresma, Paula G. F. ^[1] ; dos Santos, Willian O. ^[1] ; List, Edward O. ^{[3, 4]} ; Kopchick, John J. ^{[3, 4]} ; Perello, Mario ^[2] ; Donato, Jr., Jose ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, BR-05508000 Sao Paulo, SP - Brazil

^[2] Multidisciplinary Inst Cell Biol, Lab Neurophysiol, RA-1900 La Plata, Buenos Aires - Argentina

^[3] Ohio Univ, Edison Biotechnol Inst, Athens, OH 45701 - USA

^[4] Ohio Univ, Heritage Coll Osteopath Med, Athens, OH 45701 - USA

• Document type: Journal article
• Source: Endocrinology; v. 162, n. 7 JUL 2021.
• Web of Science Citations: 0

Abstract

Ghrelin stimulates both GH secretion and food intake. The orexigenic action of ghrelin is mainly mediated by neurons that coexpress agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). GH also stimulates food intake and, importantly, ARH(AgRP/NPY) neurons express GH receptor (GHR). Thus, ghrelin-induced GH secretion may contribute to the orexigenic effect of ghrelin. Here, we investigated the response to ghrelin in male mice carrying GHR ablation specifically in neurons (brain GHR knockout {[}KO] mice) or exclusively in ARH(AgRP/NPY) neurons (AgRP GHR KO mice). Although brain GHR KO mice showed normal ghrelin-induced increase in plasma GH levels, these mutants lacked the expected orexigenic response to ghrelin. Additionally, brain GHR KO mice displayed reduced hypothalamic levels of Npyand Ghsr mRNA and did not elicit ghrelin-induced c-Fos expression in the ARH. Furthermore, brain GHR KO mice exhibited a prominent reduction in AgRP fiber density in the ARH and paraventricular nucleus of the hypothalamus (PVH). In contrast, AgRP GHR KO mice showed no changes in the hypothalamic Npy and Ghsr mRNAs and conserved ghrelin-induced food intake and c-Fos expression in the ARH. AgRP GHR KO mice displayed a reduced AgRP fiber density (similar to 16%) in the PVH, but this reduction was less than that observed in brain GHR KO mice (similar to 61%). Our findings indicate that GHR signaling in the brain is required for the orexigenic effect of ghrelin, independently of GH action on ARH(AgRP/NPY) neurons. (AU)

• FAPESP's process: 20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions
• Grantee: Jose Donato Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/20897-3 - Role of orexin neurons as mediators of the central effects induced by growth hormone
• Grantee: Frederick Wasinski
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/25281-3 - Effects of growth hormone on POMC, cholinergic and hypothalamic paraventricular nucleus neurons: implications for energy and glycemic metabolism control
• Grantee: Paula Gabriele Fernandes Quaresma Bergonsi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral