Mechanisms of adipose tissue dysfunction in obesity: role of lipid-mediated metabolic inflammation in Adipose Tissue Macrophages.

This research programme focuses on macrophage lipid metabolism. Our previous research showed that a distinct metabolic form of inflammation, caused by dysregulated cellular lipid metabolism, occurs in AT macrophages (ATMs) during obesity. Adipose tissue (AT) function is impaired by inflamed macrophages, contributing to obesity-associated cardiometabolic comorbidities (CMCs). Preventing or resolving "metabolic inflammation" can improve AT function and avert CMCs. We will investigate the pathogenic relevance of three pathways that act in concert to regulate macrophage lipid metabolism: i) preferential incorporation of saturated fatty acids (SFAs) or polyunsaturated FAs (PUFAs) into membrane lipids (Lands' cycle), ii) the role of intracellular FA remodelling and iii) the partitioning of PUFAs to different cellular compartments during the resolution of metabolic inflammation. We will combine cellular and in vivo murine models coupled with state-of-the-art lipid profiling methods and data analysis approaches to investigate how defective macrophage lipid metabolism leads to AT dysfunction and CMCs. Our programme will identify critical mechanistic factors driving metabolic inflammation, thus providing new evidence-based targets to develop drugs to dissociate obesity from its CMCs and identify putative mechanistic biomarkers to stratify obese patients according to their susceptibility to cardiometabolic risk.