Effects of intracerebroventricular irisin administration on the modulation of microglial and hypothalamic neuroinflammation through the TLR4 signaling pathway in obese C57BL/6 mice

• Grant number: 21/01448-1
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): March 01, 2022
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Kelly Cristina Pereira Bem
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

A diet rich in long-chain saturated fatty acids is capable of causing an inflammatory state in the central nervous system (CNS) by several means, among them elements the activation of the Toll-like receptor 4 (TLR4), resulting in the release of pro-inflammatory cytokines. Hypothalamic nuclei, related to the control of hunger and satiety, are usually compromised and become less responsive to the hormones leptin and insulin, contributing to the hyperphagic and obese phenotype. The activation of microglia is decisively involved in neurodegeneration, observed in many neuroinflammatory pathologies, due to the overproduction of neurotoxic factors, such as the release of inflammatory cytokines, including TNF-±, IL-1² and IL-6. On the other hand, physical activity has an anti-inflammatory action, and among the several known types, its effect stands out through the action of myokines released by skeletal muscle. Irisin is an adipomyokine, derived from the cleavage of FNDC5 (Fibronectin Type III Domain 5) that has already known anti-inflammatory properties through the negative regulation of components of the TLR4/MyD88 pathway in some tissues. With all this in mind, using data from single cell messenger RNA sequencing assays (single cell RNA sequencing - scRNAseq) we investigated an expression heterogeneity of Fndc5, Itga5 and Itgb5 (says for the expression of the ±V/²5 integrin irisin receptor) and Trl4 in the hypothalamus of adult mice through bioinformatics analysis and we identified that the presence of the Fndc5 gene predominantly in neurons, already the expression of the Itga5, Itgb5 and Tlr4 genes, in microglia. Therefore, considering the role of microglia in neuroinflammation in response to saturated fatty acids, the objective of this study is to evaluate the effects of intracerebroventricular (ICV) administration on the modulation of microglial and hypothalamic neuroinflammation by inhibiting the TLR4 signaling pathway in obese C57BL/6 mice. This project will contribute to a better understanding of the anti-inflammatory action of irisin in the hypothalamus, highlighting the role of microglia in neuroinflammation and how the restoration of this process can positively impact the central sensitivity to the hormones leptin and insulin in obese subjects.