THE INHIBITION OF THE THROMBOXANE RECEPTOR (TP) IN ADIPOCYTES STIMULATES THERMOGENESIS AND IMPROVES GLYCEMIC HOMEOSTASIS.

• Grant number: 24/01061-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2024
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Gabriel Salerno Costa
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Adipose tissue, composed of specialized cells known as adipocytes, is classified into white (WAT), brown (BAT), and beige (BeAT) adipose tissue. These tissues differ morphologically: WAT is formed by unilocular adipocytes, whereas BAT and BeAT contain multilocular adipocytes rich in mitochondria. BeAT arises from WAT in response to stimuli such as cold exposure, through a process called "browning," in which white adipocytes acquire thermogenic features similar to those of BAT. In addition to their endocrine role through adipokine secretion, BAT and BeAT have an additional specialization: they are thermogenic fat depots. Thermogenesis is the process by which these tissues produce heat, mainly regulated by uncoupling protein 1 (UCP1), which promotes substrate oxidation without ATP production, thus contributing to body temperature maintenance and metabolic balance. Activation of thermogenic mechanisms in these fat depots has been shown to regulate cardiometabolic diseases, such as obesity and insulin resistance. Therefore, identifying targets such as receptors that regulate adipose tissue thermogenesis is essential. Literature data show that the thromboxane receptor (TP) is highly expressed in the adipose tissue of individuals with obesity and insulin resistance, and global TP deletion in knockout (KO-TP) mice results in increased energy expenditure and improved insulin sensitivity. Our research group has shown a significant relationship between TP receptors and thermogenesis. The use of TP antagonists, such as TPA, in high-fat diet (HFD)-fed mice improved glucose tolerance, reduced fasting glycemia and circulating insulin, decreased body weight, and improved lipid profile. Previous data from our lab also revealed that cold exposure significantly increases TP protein in wild-type animals, whereas AdipoqCRE-TPflox mice exhibit increased energy expenditure and oxygen consumption. We hypothesize that TP receptor activation negatively modulates thermogenic pathways in BAT and BeAT, and that specific TP deletion in adipose tissue enhances thermogenesis, increasing energy expenditure and improving glycemic homeostasis. This project aims to investigate the role of the TP receptor in the regulation of thermogenesis and glycemic homeostasis using adipose-specific TP knockout mice (AdipoqCRE-TPflox). This model will be essential for understanding how modulation of TP signaling impacts thermogenic activation and energy metabolism. Specifically, we will examine whether TP deletion in adipocytes enhances brown and beige thermogenic capacity, affects glycemic control, and identify intracellular signaling pathways mediated by TP in adipocytes. This project is expected to provide crucial insights into the role of TP in thermogenesis and glucose homeostasis, offering new therapeutic perspectives for treating obesity and insulin resistance.