GH-Releasing Hormone Neurons Regulate the Hypothalamic-Pituitary-Somatotropic Axis via Short-Loop Negative Feedback

Autor(es)

Gusmao, Daniela O. ; de Sousa, Maria E. ; de Sousa, Ligia M. M. ; Silva, Josiane N. ; Frazao, Renata ; List, Edward O. ; Kopchick, John J. ; Donato Jr, Jose

• Tipo de documento: Artigo Científico
• Fonte: Endocrinology; v. 166, n. 5, p. 14-pg., 2025-05-01.

Resumo

Growth hormone (GH)-releasing hormone (GHRH) neurons are master regulators of GH secretion. However, the role of these cells in controlling pituitary GH secretion through short-loop negative feedback has not yet been fully clarified. Thus, GHRH-specific GH receptor (GHR) knockout (GHRH Delta GHR) mice were generated, and possible consequences on GH secretion and body growth were determined. Approximately 60% of arcuate nucleus GHRH neurons exhibited GH-induced STAT5 phosphorylation, a marker of GHR-expressing cells. This response was practically eliminated in GHRH Delta GHR mice. GHR ablation in GHRH-expressing cells increased body weight, lean mass, and naso-anal length in male and female mice without affecting fat mass. The higher body growth of GHRH Delta GHR mice was associated with increases in GH secretion, mainly via higher pulsatile GH secretion and GH pulse amplitude. GHRH Delta GHR female mice also showed increased GH pulse frequency and basal (non-pulsatile) secretion compared to control females. Liver Igf1 expression was increased only in GHRH Delta GHR male mice. Mice carrying ablation of the insulin-like growth factor-1 (IGF-1) receptor (IGF1R) or both GHR and IGF1R in GHRH-expressing cells were generated. The increases in body growth and serum IGF-1 levels were significantly higher in GHRH Delta GHR/IGF1R mice compared to GHRH Delta GHR mice but similar to levels observed in GHRH Delta IGF1R mice. Electrophysiological experiments showed no acute changes in the activity of GHRH neurons after GH or IGF-1 exposure. In conclusion, GH feeds back on GHRH cells to control the hypothalamic-pituitary-somatotropic axis. However, IGF1R signaling prevails over GHR as the primary signal sensed by GHRH neurons to regulate GH secretion. (AU)

• Processo FAPESP: 20/01318-8 - Sistema nervoso central como um alvo do hormônio do crescimento para a regulação de múltiplas funções biológicas
• Beneficiário: Jose Donato Junior
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 21/11551-4 - Estudo dos circuitos hipotalâmicos que regulam o metabolismo e o sistema endócrino
• Beneficiário: Josiane do Nascimento Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 22/11262-5 - Envolvimento de neurônios kisspeptinérgicos hipotalâmicos em disfunções reprodutivas devido a alterações do eixo GHIGF-1
• Beneficiário: Renata Frazão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/03316-5 - Avaliação da importância da transmissão GABAérgica e dopaminérgica sobre os neurônios que expressam o hormônio liberador de GH para o controle da secreção de GH
• Beneficiário: Daniela de Oliveira Gusmão
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 23/11833-5 - Mecanismos fisiológicos que controlam a secreção de GH: identificação do gerador de pulsos e dos eventos associados à maturação do eixo somatotrópico
• Beneficiário: Lígia Maria Martins de Sousa
• Modalidade de apoio: Bolsas no Brasil - Doutorado