Characterization of the endothelial expression of CXCL12 in high-fat diet-induced hypothalamic inflammation in mice

• Grant number: 24/00572-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2024
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Natália Ferreira Mendes
• Grantee: Vinicius Stefanini Mantovan
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The overconsumption of saturated fats in the diet leads to the chemotaxis of immune cells to various tissues, including the hypothalamus, the central regulator of energy homeostasis. In mice, the consumption of a high-fat diet (HFD) results in endothelial dysfunction of fenestrated capillaries, found in the median eminence (ME), and the blood-brain barrier (BBB), which is distributed throughout the hypothalamic parenchyma. Consequently, there is a reorganization of the microvasculature in the hypothalamus, facilitating the passage of substances and peripheral immune cells into the central nervous system (CNS), which are attracted by chemotaxis. In silico analyses of the transcriptome of CCR2 monocytes isolated from the hypothalamus of mice fed a HFD revealed a differential gene expression (DGEs) of various genes related to chemotaxis, such as the chemokine CXCL12, which is widely expressed in endothelial cells in the arcuate nucleus of the hypothalamus (ARC) and the ME. Although it has been demonstrated that the expression of CXCL12 is regulated by hypoxia-inducible factor-1 (HIF-1) in various systems, it is not yet known whether its modulation during diet-induced hypothalamic inflammation affects the expression of CXCL12. In this study, we will investigate whether a HFD is capable of modulating CXCL12 endothelial expression in the ARC/ME, and whether the HIF-1 deletion in the endothelium, through the Cre-LoxP system, affects the expression of CXCL12. This study will contribute to obtaining unprecedented data on the role of CXCL12 in endothelial dysfunction during hypothalamic inflammation.