Growth hormone receptor in VGLUT2 or Sim1 cells regulates glycemia and insulin sensitivity

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Tavares, Mariana R. ; dos Santos, Willian O. ; Amaral, Andressa G. ; List, Edward O. ; Kopchick, John J. ; Alves, Guilherme A. ; Frazao, Renata ; dos Santos, Jessica D. M. ; Cruz, Alessandra G. ; Camporez, Joao Paulo ; Donato Jr, Jose

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 121, n. 52, p. 11-pg., 2024-12-24.

Abstract

Growth hormone (GH) has several metabolic effects, including a profound impact on glucose homeostasis. For example, GH oversecretion induces insulin resistance and increases the risk of developing diabetes mellitus. Here, we show that GH receptor (GHR) ablation in vesicular glutamate transporter 2 (VGLUT2)- expressing cells, which comprise a subgroup of glutamatergic neurons, led to a slight decrease in lean body mass without inducing changes in body adiposity. VGLUT2 triangle GHR mice exhibited reduced glycemia and improved glucose tolerance and insulin sensitivity. Among different glutamatergic neuronal populations, we found that GHR inactivation in Sim1-expressing cells recapitulated the phenotype observed in VGLUT2 triangle GHR mice. Furthermore, Sim1 triangle GHR" mice exhibited reduced endogenous glucose production and improved hepatic insulin sensitivity without alterations in whole- body or muscle glucose uptake. Sim1 triangle GHR mice were protected against acute but not chronic diabetogenic effects of exogenous GH administration. Pharmacological activation of ATP- sensitive potassium channels in the brain normalized blood glucose levels in Sim1 triangle GHR mice. In conclusion, the absence of GHR signaling in VGLUT2/Sim1- expressing cells causes a persistent reduction in glycemia and improves hepatic insulin sensitivity. Central glucose- sensing mechanisms are likely involved in the reduced glycemia exhibited by Sim1 triangle GHR mice. The current findings uncover a mechanism involved in the effects of GHR signaling in regulating glucose homeostasis. (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: 21/08792-0 - Disfunction of growth hormone secretion effects in the hypothalamic kisspeptin system
• Grantee: Guilherme Andrade Alves
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/04956-5 - Impact of the estrogen receptor alpha on Non-Alcoholic Fatty Liver Disease and energetic metabolism of the liver
• Grantee: João Paulo Gabriel Camporez
• Support Opportunities: Research Grants - Young Investigators Grants
• 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: 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