281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism

The transmembrane protein, cluster of differentiation 36 (CD36), facilitates tissue fatty acid uptake and is highly expressed in a variety of different cell types, including endothelial cells (ECs). Loss of EC Cd36 reduces parenchymal long-chain fatty acid uptake and improves whole-body glucose tolerance and insulin sensitivity; however, the mechanisms by which this occurs remain unclear. Here, we report that EC-specific deletion of Cd36 in chow-fed male mice (EC-Cd36^-/-) leads to significant reductions in whole-body fat utilization during fasting, subsequently increasing plasma non-esterified fatty acid levels by 30% (P<0.05 vs. Cd36^fl/fl). We performed hyperinsulinemic-euglycemic clamp studies, using [¹³C₆]glucose as the infusate, and found that loss of EC Cd36 improved whole-body insulin sensitivity by 15% (P<0.05 vs. Cd36^fl/fl) due to a 40-50% increase in insulin-stimulated glucose uptake in heart and brown adipose tissue (both P<0.05 vs. Cd36^fl/fl). Consistent with enhanced rates of glucose transport, EC-Cd36^-/- mice displayed a significant 20% increase in relative rates of myocardial pyruvate dehydrogenase oxidation to citrate synthase flux (V_PDH/V_CS) compared to Cd36^fl/fl controls; in contrast, mitochondrial V_PDH/V_CS was unaffected in liver and skeletal muscle. Interestingly, improvements in whole-body insulin sensitivity due to loss of EC Cd36 was also associated with 20% reductions in fasting plasma glucose concentrations and hepatic glucose production (both P<0.05 vs. Cd36^fl/fl), which could be attributed to a significant 20% decrease in hepatic acetyl-CoA content.

Conclusion: Taken together, these results demonstrate a key role for EC Cd36 in regulating parenchymal fuel selection and hepatic glucose production and provide insight into the mechanisms by which EC Cd36 controls systemic glucose and lipid metabolism.