Increased GH Secretion and Body Growth in Mice Carrying Ablation of IGF-1 Receptor in GH-releasing Hormone Cells

Author(s)

Gusmao, Daniela O. ; de Sousa, Maria E. ; Tavares, Mariana R. ; Donato, Jose

• Document type: Journal article
• Source: Endocrinology; v. 163, n. 11, p. 13-pg., 2022-10-11.

Abstract

Growth hormone (GH) secretion is controlled by short and long negative feedback loops. In this regard, both GH (short-loop feedback) and insulin-like growth factor 1 (IGF-1; long-loop feedback) can target somatotropic cells of the pituitary gland and neuroendocrine hypothalamic neurons to regulate the GH/IGF-1 axis. GH-releasing hormone (GHRH)-expressing neurons play a fundamental role in stimulating pituitary GH secretion. However, it is currently unknown whether IGF-1 action on GHRH-expressing cells is required for the control of the GH/IGF-1/growth axis. In the present study, we investigated the phenotype of male and female mice carrying ablation of IGF-1 receptor (IGF1R) exclusively in GHRH cells. After weaning, both male and female GHRH(Delta IGF1R) mice exhibited increases in body weight, lean body mass, linear growth, and length of long bones (tibia, femur, humerus, and radius). In contrast, the percentage of body fat was similar between control and GHRH(Delta IGF1R) mice. The higher body growth of GHRH(Delta IGF1R) mice can be explained by increases in mean GH levels, GH pulse amplitude, and pulse frequency, calculated from 36 blood samples collected from each animal at 10-minute intervals. GHRH(Delta IGF1R) mice also showed increased hypothalamic Ghrh mRNA levels, pituitary Gh mRNA expression, hepatic Igf1 expression, and serum IGF-1 levels compared with control animals. Furthermore, GHRH(Delta IGF1R) mice displayed significant alterations in the sexually dimorphic hepatic gene expression profile, with a prevailing feminization in most genes analyzed. In conclusion, our findings indicate that GHRH neurons represent a key and necessary site for the long-loop negative feedback that controls the GH/IGF-1 axis and body growth. (AU)

• FAPESP's process: 20/10102-9 - Study of the effects induced by GH receptor ablation in neurons of the lateral hypothalamic area
• Grantee: Mariana Rosolen Tavares
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• 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: 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