Uncovering the transcriptional deactivation of brown fat thermogenesis

• Applicant: Anna Sophia Kirstein
• Subject Area: Endocrinology, Diabetology, Metabolism ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520412725

Brown adipose tissue (BAT) has emerged as a promising therapeutic target to improve metabolic disorders associated with obesity. Activated upon cold-exposure, its capacity for non-shivering thermogenesis leads to higher energy expenditure, which is favourable in conditions of obesity. Most studies focus on the activation process. β-adrenergic signaling is known to activate the thermogenic program, but translation into clinical applications has been hampered by limited efficacy and side-effects. In contrast, mechanisms leading to the deactivation of BAT upon exposure to thermoneutrality are incompletely understood. The overall objective of this project is to uncover the transcriptional mechanisms turning down BAT thermogenic activity, to identify targets for preventing this process. I will specifically focus on the role of the temperature sensitive transcriptional regulators, Inhibitor of DNA Binding 1 (Id1) and Id3. Id proteins bind and deactivate transcription factors, but the targets of Id1 and 3 as well as their role in BAT are unknown. I therefore aim to delineate the role of these two factors in regulating cellular metabolism in BAT by 1) Investigating whether the induction of these factors in mouse BAT will prevent its deactivation. This will be facilitated via recombinant adeno-associated virus (rAAV) mediated Id1 and Id3 induction and RNA sequencing. 2) Finding the binding partners of Id1 and Id3 in BAT via co-immunoprecipitation and proteomics analysis to identify the downstream transcription factors inhibited through their binding. This will enable a mechanistic understanding of how Id1 and Id3 influence BAT deactivation. 3) Performing ID1 and ID3 downregulation via siRNA and induction via CRISPR activation (CRISPRa) in primary and immortalized human brown adipocytes to measure the impact on energy expenditure in human model systems. The identification of drugable targets for obesity intervention is highly relevant, given the emerging prevalence of metabolic disorders. The research will increase the fundamental understanding of BAT deactivation, which holds therapeutic potential to improve metabolic health.

• DFG Programme: WBP Fellowship
• International Connection: Denmark
• Host: Professor Dr. Brice Emanuelli