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

Author(s)

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

• Document type: Journal article
• Source: Endocrinology; v. 166, n. 5, p. 14-pg., 2025-05-01.

Abstract

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)

• 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: 21/11551-4 - Study of hypothalamic circuits that regulate metabolism and the endocrine system
• Grantee: Josiane do Nascimento Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/11262-5 - Involvement of hypothalamic kisspeptin neurons in reproductive dysfunctions due to changes in the GH-IGF-1 axis
• Grantee: Renata Frazão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/03316-5 - Evaluation of the importance of GABAergic and dopaminergic transmission in neurons that express the growth hormone-releasing hormone to the control of GH secretion
• Grantee: Daniela de Oliveira Gusmão
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 23/11833-5 - Physiological mechanisms that control GH secretion: identification of the pulse generator and events associated with somatotropic axis maturation
• Grantee: Lígia Maria Martins de Sousa
• Support Opportunities: Scholarships in Brazil - Doctorate