Deciphering determinants of white adipocyte lipid turnover in cardiometabolic disorders

The main function of white adipose tissue (WAT) is to store (lipogenesis) and release (lipolysis) energy.

In humans, both pathways are under hormonal control where insulin stimulates lipogenesis and inhibits lipolysis, whereas catecholamines and atrial natriuretic peptide (ANP) activate lipolysis. The balance between lipogenesis and lipolysis determines WAT lipid turnover and thereby its storage capacity.

By comparing WAT from people with and without atherosclerosis, our preliminary data has identified that the two groups differ in their ability to turnover lipids.

More specifically, subjects with atherosclerosis display reduced responsiveness not only to insulin, but also to catecholamines and ANP.

Based on these observations, we hypothesize that this “multi-hormone resistance” promotes cardiometabolic complications via ectopic lipid deposition and impacts on the response to antidiabetic drugs.

However, whether the attenuated response to hormones and drugs depends on a general dysregulation in all fat cells or in specific adipocyte subtypes is unclear.

To test this, we will perform detailed phenotyping of clinical intervention studies using spatial transcriptomics and organellar proteomics and perform state-of-the-art experiments in human adipocyte 3D models.

By unravelling the mechanisms underlying inter-individual variations in lipid turnover, our project can improve diagnostic and therapeutic precision in people suffering from common cardiometabolic complications.