Mapping White Adipose Tissue lipid UPtake to cardiovascular disease initiation

forthcoming

Obesity is associated with adipose tissue dysfunction and greatly increased risk for developing not only metabolic pathologies but also cardiovascular disease (CVD). While insulin resistance and adipose-derived cytokines are established drivers of vascular dysfunction and atherosclerosis initiation, the direct contribution of changes in white adipose tissue (WAT) lipid uptake on vascular health has remained unresolved, yet would open up novel treatment opportunities. My lab has built an arsenal of unique transgenic mouse models and organotypic human in vitro systems for mapping WAT lipid dynamics, yielding exciting preliminary data and the opportunity for us to now address this key question. In WATs-UP, we will untangle the mechanisms reducing WAT fatty acid uptake in obesity on a cellular, molecular and systemic level across humans and mice, and map the consequences for vascular function and atherosclerosis initiation. Specifically, we will harness insights from novel transgenic mouse lines developed by my lab to show how obesity-driven adipocyte enlargement alters WAT uptake of cholesterol and fatty acids; use our human 3D model of unilocular adipocytes to map how increased cholesterol uptake during obesity impairs adipocyte fatty acid metabolism; and transgenic mice to determine the relative contribution of triglyceridemia versus other WAT-derived cardiovascular risk factors for vascular lipid accumulation. Together, WATs-UP will significantly advance our molecular understanding of how weight gain fuels triglyceridemia and vascular dysfunction, opening novel therapeutic opportunities to combat both metabolic and CVD in obesity. With my combined expertise in metabolism and vascular biology, and the unique experimental in vivo and in vitro models developed by us, we are in a prime position to resolve the mechanisms controlling lipid dynamics of the obese WAT and their consequences for cardiovascular health, and identify novel preventive targets against them.