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  • Project No: #OxKEN-2021/23
  • Intake: OxKEN

PROJECT OVERVIEW

The metabolic risk of obesity leading to type 2 diabetes and premature heart disease is conveyed by the imbalance in the opposing function of upper and lower body fat stores.  An upper body fat and visceral fat accumulation are strongly associated with metabolic complications and chronic inflammation whereas expansion of lower body fat stores is protective. This fits well with physiological studies observing functional differences between abdominal and gluteofemoral adipose tissue (AT) but the key drivers for sex-specific expansion of the protective lower body fat stores are poorly understood. In type 2 diabetes, chronic inflammation in AT is caused by the enhanced recruitment of pro-inflammatory macrophages. The role of an innate immune response in AT is understood for cellular turnover but less is known about the role of immune cells in tissue remodelling. Recent pilot data from our laboratory suggest the involvement of an immunometabolic cross talk between tissue macrophages and adipocyte progenitor cells stimulated by the female specific sex hormone oestrogen. Using a newly developed co-culture system of iPS-derived macrophages and human regional-specific adipocyte progenitor cells we showed that oestrogen is inducing a phenotypic change in the macrophages, but only in the presence of gluteofemoral pre-adipocytes and not with abdominal cells. In turn, only in the presence of macrophages, oestrogen induced a proliferative response in the gluteofemoral pre-adipocytes. With these findings we postulate a priming signal from gluteofemoral pre-adipocytes to macrophages and the release of a proliferative signal from the macrophages. The aim of this studentship is to characterise the cross-talk between tissue macrophages and adipocytes to understand the regulation of tissue remodelling and inflammation.

The project will involve the following steps:

  • Establish and fine-tune the co-culture and organoid systems between iPS-derived macrophages and human adipose cells.
  • Characterise the phenotypic changes of macrophages when in contact with adipocytes, in the presence or absence of oestrogen, towards pro-inflammatory polarization, and its impact on tissue remodelling
  • Identify signals exchanged between macrophages and adipocytes and signalling pathways activated that convey a proliferative response on gluteofemoral pre-adipocytes in the presence of oestrogen 
  • Access human whole AT from humans with defined fat distribution (recall-by-phenotype in the Oxford Biobank) to provide in vivo verification of findings.

This project has great potential for discovery of poorly understood signals in normal sex-specific human tissue development and novel therapeutic strategies for immunometabolic disease.

KEYWORDS

Inflammasome, matrix remodelling, single cell RNASeq, android and gynoid

TRAINING OPPORTUNITIES

  • Human adipocyte cell culture systems including organoids
  • RNA silencing and genetic modification of iPS macrophages and adipocytes
  • In vivo and vitro tissue/cell phenotyping, microscopy, RNASeq
  • Human genetic models, handling human tissues 

KEY PUBLICATIONS

CONTACT INFORMATION OF ALL SUPERVISORS

Fredrik Karpe

Jelena Bezbradica Mirkovic

Marijana Todorcevic