The involvement of hypothalamic Sorbs1 in the metabolic phenotype of mice undergoing caloric restriction

• Grant number: 24/21229-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2025
• End date: April 30, 2029
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Licio Augusto Velloso
• Grantee: Gabriel Calheiros Antunes
• 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 and type 2 diabetes are currently global epidemics. According to data from the World Health Organization, in 2022, there were 1 billion adults with obesity worldwide, with a projection for 2035 of 1.8 billion people with obesity. Obesity results from the excessive accumulation of fat and is associated with insulin resistance, contributing to severe metabolic disorders. Adipose tissue not only stores fat but also regulates insulin sensitivity through the release of bioactive molecules, such as leptin and inflammatory cytokines. Additionally, obesity leads to a state of hypothalamic inflammation, where the processes regulating hunger and satiety are compromised, aggravating the state of obesity and type 2 diabetes. Treating obesity and type 2 diabetes requires effective interventions, with caloric restriction being one of the strategies that yield the most consistent results, leading to weight loss and improved insulin sensitivity. However, adherence to this strategy is often low, and emotional and social factors can hinder the maintenance of healthy habits in the long term. Nevertheless, understanding the mechanistic impact of caloric restriction could help identify new therapeutic targets. One of these is the Sorbs1 gene, which plays an important role in regulating glycemic homeostasis and metabolism and is associated with insulin sensitivity. The hypothalamus, an important regulator of appetite and metabolism, controls satiety and hunger through the action of anorexigenic neurons (POMC) that are involved in reducing food intake and orexigenic neurons (AgRP) that increase hunger, consequently raising energy consumption, serving as key regulators of energy balance. The communication between these neurons and other brain areas integrates signals that modulate eating behavior and energy expenditure, highlighting the complexity of body weight regulation. Thus, it is essential to investigate new therapeutic targets that modulate the function of hypothalamic tissue for controlling food intake and energy metabolism. In this project, we will evaluate the expression and function of Sorbs1 in the hypothalamus. In the first stage of the study, we will use histology with immunofluorescence and analysis by confocal microscopy to precisely define the expression sites of Sorbs1 in the hypothalamus. Next, we will assess the impact of a high-fat diet on the expression of Sorbs1 in the hypothalamus, using immunofluorescence in histology and real-time PCR. If there is expression of Sorbs1 in POMC and/or AgRP neurons, we will use the Cre-Lox method, through viral vectors, to inhibit or increase the expression of Sorbs1 specifically in each of the subpopulations of neurons. The animals subjected to the interventions will then be phenotyped for weight gain, food intake, glucose tolerance, energy expenditure, oxygen consumption, carbon dioxide production, and spontaneous movement. We believe that defining the role of Sorbs1 in the hypothalamus could contribute to advancing the mechanistic understanding of obesity and potentially reveal new therapeutic targets.