Body fat distribution, obesity, and cardiometabolic disease risk: unravelling differences in the inflammatory and oxidative phenotype between upper and lower body adipose tissue in humans

Obesity is associated with adipose tissue (AT) dysfunction, characterised by adipocyte hypertrophy and chronic low-grade inflammation, and an increased cardiometabolic risk. Abdominal fat mass accumulation in obesity is an important predictor of insulin resistance and related complications. In contrast, lower-body fat has protective functional properties that are associated with an improved metabolic and cardiovascular risk profile in both men and women. Therefore, it is tempting to postulate that differences in the inflammatory signatures between upper and lower-body AT may determine the disease risk associated with a certain body fat distribution pattern.

Only few studies have investigated potential differences in the inflammatory phenotype of upper and lower-body AT. Although no major differences in gene expression of inflammatory markers were found between abdominal and gluteal subcutaneous AT, it has been demonstrated that in vivo interleukin (IL)-6 release from gluteofemoral AT was lower than from abdominal subcutaneous AT both in men and women. The latter findings suggest that lower-body AT may have a more beneficial inflammatory phenotype. However, it remains to be established whether there are differences in the depot-specific secretion of other (anti-)inflammatory factors.

Recent evidence suggests that AT oxygenation, determined by the local oxygen supply and consumption balance, may be a key factor determining the AT phenotype. In rodent models of obesity, AT oxygen partial pressure (AT pO2) is reduced. However, we have challenged the concept of AT ‘hypoxia’ in human obesity, demonstrating that AT pO2 was higher rather than lower in obese compared to lean subjects, despite lower blood flow (oxygen supply), and was positively correlated with AT inflammation and insulin resistance. Furthermore, diet-induced weight loss decreased abdominal subcutaneous AT pO2, paralleled by improved insulin sensitivity in humans . Unpublished data from the Goossens laboratory show that AT pO2 was lower in femoral than abdominal subcutaneous AT in overweight/obese women. Moreover, exposure to low physiological pO2 (5% O2) decreased pro-inflammatory gene expression (e.g. IL-6) in a depot-independent manner in differentiated abdominal and femoral human adipocytes

Here, we hypothesize that there are intrinsic differences in the in vivo secretion of (anti-) inflammatory factors and adipokines between abdominal and femoral adipose tissue due to depot-differences in oxygen metabolism in humans. Furthermore, we propose that altered adipose tissue oxygen metabolism in obesity contributes to an unfavourable adipose tissue inflammatory profile.

Aims
We aim to investigate the differences in oxygen metabolism and inflammatory profile between upper and lower-body AT in humans. We will integrate human in vivo studies and mechanistic human cell culture experiments to address the following key objectives:
1. To compare the in vivo release of pro- and anti-inflammatory factors and adipokines across upper body (abdominal) and lower-body (gluteofemoral) subcutaneous AT in lean and obese women.
2. To elucidate whether in vivo upper and lower-body AT oxygen metabolism is related to the inflammatory signatures of these fat depots in lean and obese women.
3. To investigate the effects of prolonged exposure to various degrees of oxygen tension on the expression and secretion of inflammatory factors in differentiated human AT-derived mesenchymal stem cells (hMADS), obtained from the in vivo studies.

This research project will be performed at the University of Birmingham (UK) and Maastricht University (The Netherlands). Therefore, the appointed PhD student will be working at both institutes for a certain part of the project.

Enquiries and applications should be directed to the College MDS Graduate School at [Email Address Removed]

To apply, please send:

• A Detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree transcripts;
• Evidence of your proficiency in the English language, if applicable.