The role of Ric-8b in energetic homeostasis of brown adipose tissue

• Grant number: 24/18873-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Camilly Vitória Barbosa Pires
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The recruitment and activation of brown adipose tissue (BAT) is one of the main means of controlling and maintaining body weight and glycemic homeostasis. A key protein responsible for BAT thermogenesis, uncoupling protein 1 (UCP1), is regulated by norepinephrine released by sympathetic terminals during cold exposure. The presence of norepinephrine and its interaction with beta-adrenergic receptors increases cAMP production through the G¿s protein (guanine nucleotide-binding protein alpha stimulator), culminating in the activation of thermogenic and metabolic pathways in BAT. Given the presence of BAT in adult humans, together with the reduction of BAT activity in obesity and diabetes, understanding the molecular mechanisms that regulate the activity of this tissue becomes fundamental. Recent evidence has demonstrated novel regulators of G¿s-cAMP-mediated signaling. Some studies have shown that the Ric-8b protein (resistant to cholinesterase 8B inhibitors) acts as a molecular chaperone required for proper folding of the G¿s subunit and its assembly with ¿¿ dimers to form functional G proteins. In addition, this protein is capable of accelerating the exchange of GDP for GTP, increasing cAMP production and downstream signal transduction resulting from its activation. Despite this evidence, the function and mechanism of action of Ric-8b on the regulation of thermogenesis in BAT mediated by the ¿-adrenergic-G¿s-cAMP axis are poorly understood. Thus, we hypothesize that the cAMP-binding protein Ric8b is a central regulator of BAT mediated by norepinephrine. Thus, the proposal of this project is to investigate the role of Ric-8b in the thermogenic regulation induced by adrenergic signaling in BAT. This project will use pharmacological and physiological approaches to characterize a Ric-8b knockout mouse model in BAT and thus determine its effects on thermogenesis, energy expenditure and metabolic homeostasis. The findings of this study may provide relevant information on novel pathways involved in adaptive thermogenesis and, consequently, reveal a potential target for future therapeutic interventions.