Hypothalamic GPR139 as a potential target for the treatment of obesity

• Grant number: 23/10026-9
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2024
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: University of Birmingham
• Principal Investigator: Licio Augusto Velloso
• Grantee: Licio Augusto Velloso
• Principal researcher abroad: Davide Calebiro
• Institution abroad: University of Birmingham, England
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Obesity affects over 600 million people worldwide and, despite recent therapeutic advance in the field, projections estimate a continuous increase of its prevalence over the next decade. In this context, the identification of new targets could improve therapeutic strategies and contribute to revert the current epidemiological scenario. G protein-coupled receptors (GPCRs) are the targets for over 35% of all drugs approved for the treatment of distinct human diseases. Orphan GPCRs are of particular interest, and, in a recent exploratory study, we identified GPR139, which is expressed in hypothalamic neurons, to be involved the regulation of food intake and energy balance. The inhibition of hypothalamic GPR139 in mice resulted in increased food intake and increased body mass; therefore, we hypothesise that pharmacologically increasing GPR139 activity could reduce food intake and, consequently, body mass. In this project, we plan to explore the impact of increasing the activity of GPR139 in rodents using the recently developed small molecule TAK-041, which is a potent and selective agonist of GPR139 that crosses the blood-brain barrier. In addition, as GPR139 is expressed in both orexigenic and anorexigenic neurons of the hypothalamus, AgRP and POMC, respectively, we plan to use AgRP-cre and POMC-cre mice and an adenovirus to deliver a floxed shRNA against the GPR139 transcripts to achieve cell-specific knockdown. Moreover, we will dissect the signal transduction pathway driving the effects of GPR139 in hypothalamic neurons. For this purpose, we will employ innovative microscopy approaches and bioluminescence energy transfer (BRET) probes that allow monitoring GPCR signalling in living cells with high spatio-temporal resolution. Using these approaches, we will clarify the signalling pathways that are activated by GPR139 in a hypothalamic neuronal cell line. Upon completion, the study will advance our understating of how hypothalamic GPR139 regulates body energy balance. This could open new opportunities for exploiting GPR139 as a novel therapeutic target for obesity. (AU)