Characterization of intracellular peptides from adipose tissues of animals with brown adipose tissue activation and browning due cold-exposure and PPARg-agonist treatment

• Grant number: 21/03717-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): June 01, 2021
• Effective date (End): May 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Patrícia Reckziegel
• Grantee: Luís Felipe Galvão Valdivia
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/25943-1 - Intracellular peptides as modulators of thermogenesis-related metabolic pathways, AP.JP

Abstract

The activation of Brown Adipose Tissue (BAT) and browning (differentiation of white adipose tissue to beige) have been defined as promising mechanisms in the treatment of Obesity and associated diseases. This potential is related to the mitochondrial uncoupling protein 1 (UCP1) expressed in adipocytes under these conditions. This protein dissipates energy from ATP synthesis for heat generation, increasing energy expenditure and the use of glucose and free fatty acids by cells. So far, cold-exposure, and consequent activation of the adrenergic system, is the main stimulus for BAT activation and browning during non-shivering thermogenesis. Pharmacologically, PPARg agonists, such as rosiglitazone (experimental use only) and pioglitazone, have been shown to increase the expression of UCP1 in adipocyte. It is known that peptides are important modulators of energy metabolism, and the identification of the profile of intracellular peptides of adipose tissues during BAT activation and browning may indicate new peptides with the potential to activate BAT and induce browning. Therefore, this project aims to (1) characterize an animal model of BAT activation and browning using cold-exposure and PPARg-agonist pioglitazone treatment. In vivo analyzes of body weight, food consumption and indirect calorimetry, as well as ex vivo such as gene and protein expression of UCP1 and other markers related to thermogenesis and adipogenesis of adipocytes must prove the activation of BAT and browning. Subsequently; (2) the interscapular BAT and the inguinal white adipose tissue (more prone to browning) of these animals will be used for peptidomic analysis by mass spectrometry. Thus, we will demonstrate, in a completely innovative manner, the intracellular peptide profile of each one of these tissues under the different experimental conditions. Then, (3) we will select the peptides that are most positively altered in the activation of BAT and browning for synthesis and evaluation of their effects on oxygen consumption of isolated mitochondria from BAT, which should indicate if they are able to activate UCP1. In this way, the present project will open new perspectives of working with intracellular peptides in energy metabolism/thermogenesis, indicating new biomarkers and peptide molecules with the potential to be used in the treatment of Obesity and associated diseases. (AU)