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

Obesity and its affiliated metabolic diseases pose serious public-health challenges. However, certain patient subgroups appear protected. To halt the socio-economic burden of metabolic disease, we urgently need to understand what distinguishes the Metabolically-Healthy-Lean (MHL), Metabolically-Unhealthy-Lean (MUL), Metabolically-Healthy-Obese (MHO) and Metabolically-Unhealthy-Obese (MUO) phenotypes, and which factors promote metabolic health. Inflammation has been proposed as a target, as it is a key driver of metabolic disease. However, clinical trials show limited evidence that anti-inflammatory drugs reduce diabetes. Why is that? Inflammation consists of a pro-inflammatory phase followed by a pro-resolving phase, which are regulated by different cells/pathways. This is critical to consider when attempting a therapeutic approach. Based on my preliminary data, I hypothesise that what separates MHL/MHO from MUL/MUO are not pro-inflammatory triggers, but rather the endogenous ability of individuals to resolve inflammation. Adipose extracellular-matrix remodelling appears critical, and pro-resolving lipids promote a MUO-to-MHO switch.My overall goal is to determine molecular pathways that differentiate the MHL/MUL/MHO/MUO phenotypes (Aim 1-4), and to investigate the therapeutic potential of pro-resolving lipids (Aim 5). This multi-disciplinary project combines cutting-edge techniques with state-of-the-art translational approaches. Through my unique access to human biobanks, I will generate patient-specific cell-lines and test drug-targets ex vivo. Novel bioinformatics pipelines will produce protein/lipid/metabolite fingerprints associated with respective patient groups, ultimately providing a new approach to tackle obesity-related comorbidities. My experience in the specialised field of pro-resolving lipid biology, coupled with my lab’s unique placement at a translational site, makes me the right candidate to lead this research program.