Role of insulin signaling on GHRH neurons in the alterations in GH secretion that occur in obesity

• Grant number: 24/22859-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Jose Donato Junior
• Grantee: Gabriel Orefice de Souza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions, AP.TEM

Abstract

Growth hormone (GH) has several metabolic effects, including an anti-insulin or diabetogenic action. Consequently, excessive GH secretion induces insulin resistance and may predispose an individual to diabetes mellitus. On the other hand, obesity is characterized by a condition of low circulating GH levels (Hjelholt et al., Endocrinology and metabolism clinics of North America 49:239-250, 2020). This condition can be negative for energy homeostasis, since GH has a lipolytic effect and GH deficiency may favor the maintenance of obesity. In fact, the therapeutic potential of GH replacement as an adjuvant in the treatment of obesity has been discussed (List et al., Diabetologia 52:1647-1655, 2009; Mekala and Tritos, J Clin Endocrinol Metab 94:130-137, 2009; Huang et al., Trends Endocrinol Metab 31:642-654, 2020; Huang et al., FASEB J 35:e21269, 2021). The mechanism of action that leads to reduced GH secretion in obesity is unknown, but some authors have suggested that increased insulin levels are responsible for the suppression of GH secretion (Huang et al., Trends Endocrinol Metab 31:642-654, 2020; Huang et al., J Endocrinol 250:105-116, 2021). Given this evidence, the objective of this project is to produce insulin receptor-deficient mice in neural populations involved in the control of GH secretion, mainly in GHRH neurons. In favor of this idea, we recently demonstrated that ablation of the IGF-1 receptor causes changes in GH secretion (Gusmao et al., Endocrinology 163:bqac151, 2022). Since the insulin and IGF-1 receptors activate the same cellular signaling pathways, our hypothesis is that increased insulinemia in obesity promotes a "negative feedback" in GHRH neurons, leading to suppression of GH secretion. Thus, we will evaluate GH secretion in both animals receiving a normal diet and in others with obesity induced by consumption of a high-calorie diet. In addition, we intend to cross this insulin receptor deletion model in GHRH neurons with ob/ob (leptin-deficient) mice to determine whether the suppression of GH secretion observed in these models can be prevented by the absence of insulin signaling in GHRH neurons. We will also evaluate how this mutation may impact body weight, adiposity, and energy balance.