Influence of NFIL3 circadian pattern on thermogenesis in brown adipose tissue

• Grant number: 22/09364-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2022
• End date: July 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Carlos Henrique Grossi Sponton
• Grantee: Carlos Eduardo Pinheiro Leher
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/15025-5 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes, AP.JP

Abstract

Brown adipose tissue (BAT) is a central effector of thermogenesis and body energy homeostasis. BAT exhibits a circadian pattern of expression of clock genes (clock genes) and of genes central to thermogenic function (eg, UCP1). Transcriptome data reveal that 8% of genes expressed in BAT show a circadian behavior (fluctuation within 24 hours), twice as high as that observed for white adipose tissue. This rhythmic pattern of gene expression in BAT is directly related to the function of this tissue, since the uptake of glucose and fatty acids has a large amplitude (variation) within 24 hours. Studies in genetically modified models show that the loss of function of components of the central machinery of the circadian cycle (for example, Clock and Bmal1) present significant accumulation of lipids and reduction of thermogenic capacity in BAT, a condition that is associated with a phenotypic picture of greater weight body weight and hyperlipidemia in mice. Our data presented in scientific report 01 identified the transcription factor NFIL3 as a regulator of the thermogenic program in brown adipocytes. NFIL3 is an auxiliary component of the circadian cycle and exhibits a rhythmic pattern of gene expression in BAT. NFIL3 is directly inhibited by another important component of the circadian cycle known as REV-ERB±. Interestingly, the gene deletion of REV-ERB± (and the REV-ERB² isoform) in BAT increases the tolerance of mice in cold exposure test, a condition associated with increased UCP1 gene expression and thermogenic activity in this tissue. Furthermore, UCP1 gene expression shows a distinct circadian behavior (anti-phase) in relation to REV-ERB± in BAT. Therefore, our purpose in this project is to understand (through loss of function assays) the importance of NFIL3 for thermogenic function in BAT. This study may reveal a relationship between the circadian cycle, thermogenic function and energy homeostasis previously unknown and of great relevance as a therapeutic perspective for obesity. (AU)