Sexual dimorphisms in fat distribution: investigating oestradiol’s depot-specific effects on preadipocyte and macrophage interactions

Fat distribution is a key regulator of cardiometabolic disease risk, with biological females typically favouring fat storage in the gluteofemoral region, while males tend to store fat around the abdomen. Accumulation of gluteofemoral adiposity, particularly through hyperplastic expansion, is metabolically favourable and is thought to be promoted by the sex hormone oestradiol in females. Alterations in oestradiol concentrations, such as those occurring at menopause or during oestradiol therapy, are associated with shifts in fat distribution and subsequent changes in cardiometabolic risk. However, the mechanisms underlying these oestradiol-induced changes remain poorly understood and are complicated by the controversial literature surrounding the effects of oestradiol on adipose tissue expansion. Given the documented role of oestradiol in modulating the inflammatory phenotypes of other cells within the adipose tissue stromovascular fraction (SVF), particularly macrophages, it is essential to investigate how oestradiol may influence signalling between adipocytes and macrophages to promote depot-specific changes in adipose expansion, favouring gluteofemoral adipose tissue growth and abdominal adipose tissue regression. This thesis aimed to first characterize the depot-specific SVF population landscape using single-cell RNA sequencing (scRNASeq) on paired abdominal and gluteal adipose tissue biopsies. It then assessed oestradiol signalling in abdominal and gluteal preadipocytes using in-vitro models, and established an in-vitro co-culture system between preadipocytes and macrophages. This system facilitated the identification of oestradiol-primed communication signals that may modulate depot-specific expansion through RNA sequencing approaches. The results reveal unique transcriptional landscapes of abdominal and gluteal adipose tissue SVF and demonstrate that preadipocyte responses to oestradiol are highly depot-specific. Additionally, this work identified a range of candidate signals exchanged between preadipocytes and macrophages that may contribute to oestradiol-primed, depots-specific adipose tissue expansion. Future research should aim to functionally test these signals using the in-vitro systems developed here.