Unveiling the transcriptional regulation of GPR3 gene in brown adipocytes

• Grant number: 22/13145-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2022
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Licio Augusto Velloso
• Grantee: Vanessa de Oliveira Furino
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

Thermogenic activation of brown adipose tissue (BAT) occurs mainly by exposure to cold. This stimulus activates the sympathetic nervous system, which promotes the release of noradrenaline and stimulates ²-adrenergic receptors (²-AR). As a result, BAT increases body energy expenditure and promotes improvements in energy homeostasis. Activation of this pathway can be mimicked by the action of a selective ²3 adrenergic agonists. However, clinical evidence limits the use of this agent as a therapy for obesity due to its adverse cardiovascular effects and its low efficacy in reducing body mass. Recent data show that BAT thermogenic activity can occur through ²-AR receptor- independent pathways. In this sense, GPR3 is a constitutive subtype of stimulatory G protein- coupled membrane receptors that signal independent of a ligand. GPR3 is expressed in BAT upon cold exposure. Gain-of-function assays show that GPR3 increases energy expenditure in brown adipocytes and counteracts the deleterious effects of obesity. However, the atypical constitutive feature of GPR3 modulation requires alternative strategies for activating this receptor. GPR3 is transcriptionally regulated by fatty acids, but the transcription factors involved in this process are not known. Our preliminary data identified Nr2c1 as a potential nuclear receptor responsible for activating GPR3 gene expression. Thus, our objective for this project will be to evaluate through gain of function assays (CRISPR/Cas9) in vitro and in vivo the contribution of Nr2c1 on the transcriptional regulation of GPR3 in brown adipocytes. These results may identify a new target for thermogenic activation of BAT and combat obesity.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRUNETTA, HENVER S.; JUNG, ANNA S.; VALDIVIESO-RIVERA, FERNANDO; ZANI, STEPHENY C. DE CAMPOS; GUERRA, JOEL; FURINO, VANESSA O.; FRANCISCO, ANNELISE; BERCOT, MARCELO; MORAES-VIEIRA, PEDRO M.; KEIPERT, SUSANNE; et al. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. EMBO Journal, v. 43, n. 21, p. 22-pg., 2024-09-16. (21/08354-2, 17/17728-8, 13/07607-8, 19/21852-1, 22/00358-1, 23/07882-0, 20/14725-0, 22/13145-6, 23/00229-0)