Inflammatory resolution and remodelling of the adipose extracellular matrix: key determinants of a metabolically healthy phenotype?

Project Information

The MATRIX

Grant agreement ID: 804418

DOI

10.3030/804418

EC signature date 6 November 2018

Start date 1 September 2019

End date 28 February 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 700 002,00

EU contribution

€ 1 700 002,00

Coordinated by

AARHUS UNIVERSITET
Denmark

Periodic Reporting for period 3 - The MATRIX (Inflammatory resolution and remodelling of the adipose extracellular matrix: key determinants of a metabolically healthy phenotype?)

Reporting period: 2024-04-01 to 2025-09-30

Summary of the context and overall objectives of the project

• What is the problem/issue being addressed?
Although obesity is a clear risk factor for a person to develop metabolic disease, certain patient subgroups appear protected. Our research investigates what distinguishes metabolically healthy versus unhealthy individuals, and furthermore identifies what factors that can promote metabolic health.

• Why is it important for society?
‘The obesity epidemic poses one of the most serious public health challenges’ [World Health Organisation]. Our research aims to halt the socio-economic burden of metabolic disease.

• What are the overall objectives?
The overall objectives are to determine molecular pathways that differentiate the metabolically healthy vs unhealthy individuals (Aim 1-4), and to investigate the therapeutic potential of pro-resolving lipids (Aim 5).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have published one original article that investigated the extracellular matrix composition in health and disease (Soták and Rajan et al, Int J Mol Sci., 2022, PMID: 35008946) and a review article pinpointing species differences in adipose tissue biology between mice and human (Börgeson E et al, Front Cell Dev Biol. 2022, PMID: 36187476). We have also published a paper outlining the therapeutic potential of pro-resolving mediators in human 3D cultured adipose tissue (Sotak et al, iScience, 2022, PMID: 35789845), and we have confirmed that said compounds can affect the migration of human cells through the lymphatics (Kraft et al, FASEB J, 2022, PMID 35104001). We are now continuing this body of work and hope to share more data soon.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have demonstrated that human fat cells must be grown in 3D cultures to respond to pro-resolving lipids. Traditionally, human fat cells are differentiated from the stromal vascular fraction of homogenized tissue, but we have shown that such cells do not respond to stimuli in a manner befitting mature adipocytes, and thus they have limited applicability when evaluating drug responses. This finding goes beyond the state of the art.

In addition, we have investigated the role of adipose extracellular matrix composition, not only in metabolically healthy vs unhealthy patients, but also in lean controls. It is notoriously difficult to obtain omental adipose tissue from lean and healthy controls, as they rarely undergo the type of surgery where it is possible to access visceral fat. Through a unique collaboration, we have been able to assemble such a control group, and this demonstrates that adipose tissue fibrosis surprisingly is reduced in obese patients, as determined through several complementary experimental approaches. It was somewhat challenging to publish this data, as it challenges the current paradigm, but we succeeded and I believe that it makes an important contribution to the scientific community, and enhances our understanding of the complex changes that the adipose tissue undergoes during the expansion associated with development of severe adiposity.

We now continue to pursue our research goals, as outlined above, where we hope and believe that our research will continue to expand the state of the art of the scientific field.