Deciphering macrophage- and stem cell-driven adipose tissue remodeling as a means to treat and prevent metabolic diseases

Obesity and polycystic ovary syndrome (PCOS), a hyperandrogenism condition affecting women, are often associated with adipose tissue dysfunction, leading to ectopic lipid deposition and increased risk of metabolic diseases.

We have discovered that adipose tissue functionality is governed by macrophage-mediated intracellular collagen degradation.

This macrophage function is enhanced in female mice, and compromised in obese insulin resistant states associated with accumulation of collagen fragments that stimulate fibroinflammatory processes. Moreover, adipose tissue dysfunction is linked to impaired adipogenesis leading to enhanced adipocyte hypertrophy.

Notably, our preliminary data show that androgen excess in female mice decreases the recruitment of adipogenic stem cells partly via altered macrophage functionality.

Here, we will use human macrophages and mouse models to identify new mechanisms in the regulation of collagen-degrading macrophages.

In addition, we will establish whether and how altered stem cell and/or macrophage functionality mediate androgen excess-induced adipose tissue dysfunction in female mice.

In parallel, we will use our recently established mass spectrometry-based methodology to validate collagen fragments as biomarkers and/or mediators of adipose tissue dysfunction in man.Results from this 5-year project will open new research directions within and outside the adipose tissue field and can lead to new strategies to prevent or treat metabolic diseases.