Microvascular endothelium from the adipose tissue: DLL4 as a metabolic sensor involved in the regulation of transendothelial fatty acid fluxes

Introduction Accumulation of adipose tissue in the central part of the body arising with obesity and aging, is associated with metabolic inflexibility and the development of cardiovascular diseases. The cellular actors and pathophysiological mechanisms linking obesity/aging and cardiometabolic abnormalities remain to be clearly identified. Our data support that microvascular endothelial cells from the adipose tissue (EC-AT) are a major determinant of metabolic flexibility, in particular through their ability to regulate bidirectional fatty acid (FA) fluxes. We hypothesize that alteration of this function contributes to the emergence of cardiometabolic disorders associated with natural and accelerated aging. Objective Our objective is to gain insight into the ability of EC-AT to sense and adapt to metabolic clues and regulate FA fluxes accordingly. Ultimately, our goal is to identify original approaches targeting the endothelium to maintain and/or restore metabolic flexibility and hamper the progression of aging-related cardiovascular disorders. Among the putative molecular mechanisms involved in the regulation of transendothelial FA fluxes, we focused our attention on Notch signaling. Method We use native and primary microvascular EC isolated from human (CD45-/CD34+/CD31+) and mouse (CD45-/SCA1+/CD31+) adipose depots. Results In vivo and in vitro we observe that endothelial-Notch activity is regulated by nutritional status. In particular, the ligand DLL4 is downregulated by fasting and AMPK activation. Using human primary EC-AT, we show that DLL4 regulates long-chain FA uptake through transcriptional and non-transcriptional processes. Conclusion Our data highlight an original role for DLL4 as metabolic sensor in adipose depots that relays transcriptional and functional clues to the endothelium. In particular, DLL4 level likely defines the ability of EC-AT to rapidly adapt and handle lipid fluxes and contributes to the regulation of metabolic flexibility.