Assessment of the function of apolipoprotein-e in proopiomelanocortin neurons of the hypothalamus

• Grant number: 23/16530-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2025
• End date: February 29, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Licio Augusto Velloso
• Grantee: Natália Stinghen Tonet
• 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

Obesity is one of the most prevalent diseases on the planet, affecting more than 600 million people, and increasing the risk of developing several comorbidities, such as diabetes mellitus, high blood pressure, dyslipidemia, and cardiovascular diseases. Obesity results from a chronic process of positive energy balance, in which caloric intake overlaps energy expenditure. Hypothalamic neurons play an important role in regulating energy balance, integrating peripheral signals with neural responses that control food intake, energy expenditure, and various systemic metabolic functions. Proopiomelanocortin (POMC) neurons in the mediobasal hypothalamus act as first-order neurons, responding to hormonal and nutrient signals, and promoting reduced hunger and increased energy expenditure. Using a bioinformatics tool to evaluate transcript expression in single cells, we identified the expression of apolipoprotein-E (apoE) in part of hypothalamic POMC neurons. Systemically, apoE participates in the transport and metabolism of lipids, acting as an important component of plasma lipoprotein particles. In the central nervous system, apoE participates in the process of lipid uptake in neurons, contributing to the regulation of neuronal plasticity. There is also evidence of the involvement of apoE in the development of Alzheimer's disease. In this project we hypothesize that apoE participates in the functional regulation of POMC neurons. To explore this hypothesis, we will use POMC-Cre mice to inhibit apoE expression specifically in POMC neurons through infection with adenovirus carrying an inhibitory shRNA for apoE. The male and female mice will then be fed a conventional diet or a high-fat diet for up to 8 weeks. During the evaluation period, caloric intake, weight gain, fat mass and lean mass, O2 consumption, CO2 production, energy expenditure, glucose tolerance, insulin sensitivity, spontaneous movement, and brown adipose tissue activity will be determined. We believe that the study can contribute to advancing the understanding of hypothalamic mechanisms for regulating energy balance.