Using immune cells to combat obesity: adipose eosinophils as mediators of metabolic homeostasis

Obesity and its associated metabolic comorbidities have become a global health crisis. The chronic expansion of the adipose tissue during obesity leads to a dysregulated microenvironment, characterised by hypoxia, fibrosis, and inflammation. The adipose tissue contains a vast repertoire of immune cells, that under healthy conditions, facilitate the maintenance of metabolic homeostasis by coordinating tissue repair and remodeling, particularly in the transition from white adipose tissue to energy-burning beige adipose tissue. In this thesis, we focused on adipose eosinophils as a key player in the immune regulation of metabolic homeostasis, by focusing on their roles in promoting adipose tissue angiogenesis and thermogenesis, which expends energy and drives weight loss. Using RNA sequencing (RNA-seq) data from murine blood and adipose eosinophils, we identified the transcription factors activating transcription factor 3 (ATF3), and JUN proto-oncogene (JUN), as key regulators of the adipose eosinophil gene program. Using an immortalised human eosinophil cell line (EoL-1 cells), we found that ATF3 is involved in suppressing the inflammatory response while promoting homeostatic roles in adipose eosinophils, including driving adipose tissue angiogenesis as mediated by expression of vascular endothelial growth factor A (VEGFA). By analysing the adipose tissue of transgenic mice with elevated eosinophils both systemically and within the adipose tissue, we found a correlation between increased eosinophil number and increased VEGFA expression, increased endothelial cells, and increased uncoupling protein 1 (Ucp1) expression, indicating an elevation in thermogenic beige adipose tissue. Cold exposure is the main stimulus for beige adipose tissue activation. It is well understood that the cold activation of beige adipose tissue involves the central nervous system (CNS) conveying the cold stimulus to the sympathetic nervous systems (SNS), which drives the thermogenic response. However, we found that adipose tissue from mice exposed to cold ex vivo can still activate thermogenic gene expression, independent of the CNS. We found that this is driven, at least in part, by adipose immune cells, including eosinophils, which in response to cold exposure secrete factors which can promote thermogenesis of primary murine adipocytes in culture. RNA-seq revealed vast transcriptional changes within adipose immune cells and eosinophils alone in response to cold exposure, with the upregulation of numerous genes which encode secreted proteins. This has allowed us to generate a list of candidates for therapeutic investigation, with potential for future clinical discovery. Together, these results have cemented the role of adipose eosinophils as homeostatic cells with important roles in the maintenance of metabolic health, which could be exploited for the treatment of people with obesity and metabolic health disorders.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2024

Author dc:creator

• Spek, Annalise

• Obesity
• Eosinophil
• Immunology
• Metabolism
• Gene regulation
• Beige fat
• anzsrc-for: 310505 Gene expression (incl. microarray and other genome-wide approaches)
• anzsrc-for: 310103 Cell metabolism

Statement dc:rights

• embargoed access
• CC BY 4.0

Licence

• http://purl.org/coar/access_right/c_f1cf
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/30634

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/103390