Ablation of Growth Hormone Receptor in GABAergic Neurons Leads to Increased Pulsatile Growth Hormone Secretion

Author(s)

dos Santos, Willian O. ; Wasinski, Frederick ; Tavares, Mariana R. ; Campos, Ana M. P. ; Elias, Carol F. ; List, Edward O. ; Kopchick, John J. ; Szawka, Raphael E. ; Donato Jr, Jose

• Document type: Journal article
• Source: Endocrinology; v. 163, n. 8, p. 17-pg., 2022-08-01.

Abstract

Growth hormone (GH) acts in several hypothalamic neuronal populations to modulate metabolism and the autoregulation of GH secretion via negative-feedback loops. However, few studies have investigated whether GH receptor (GHR) expression in specific neuronal populations is required for the homeostatic control of GH secretion and energy homeostasis. In the present study, we investigated the consequences of the specific GHR ablation in GABAergic (VGAT-expressing) or glutamatergic (VGLUT2-expressing) cells. GHR ablation in GABAergic neurons led to increased GH secretion, lean mass, and body growth in male and female mice. VGAT-specific GHR knockout (KO) male mice also showed increased serum insulin-like growth factor-1, hypothalamic Ghrh, and hepatic Igf1 messenger RNA levels. In contrast, normal GH secretion, but reduced lean body mass, was observed in mice carrying GHR ablation in glutamatergic neurons. GHR ablation in GABAergic cells increased weight loss and led to decreased blood glucose levels during food restriction, whereas VGLUT2-specific GHR KO mice showed blunted feeding response to 2-deoxy-D-glucose both in males and females, and increased relative food intake, oxygen consumption, and serum leptin levels in male mice. Of note, VGLUT2-cre female mice, independently of GHR ablation, exhibited a previously unreported phenotype of mild reduction in body weight without further metabolic alterations. The autoregulation of GH secretion via negative-feedback loops requires GHR expression in GABAergic cells. Furthermore, GHR ablation in GABAergic and glutamatergic neuronal populations leads to distinct metabolic alterations. These findings contribute to the understanding of the neuronal populations responsible for mediating the neuroendocrine and metabolic effects of GH. (AU)

• 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: 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: 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