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. Cd36fl/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. Cd36fl/fl) due to a 40-50% increase in insulin-stimulated glucose uptake in heart and brown adipose tissue (both P<0.05 vs. Cd36fl/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 (VPDH/VCS) compared to Cd36fl/fl controls; in contrast, mitochondrial VPDH/VCS 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. Cd36fl/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. Disclosure L. Goedeke: None. N. Son: None. T. E. Lamoia: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. M. Kahn: None. X. Zhang: None. G. Cline: None. I. J. Goldberg: Advisory Panel; Self; Akcea Therapeutics, Arrowhead Pharmaceuticals, Inc., Consultant; Self; Esperion. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company. Funding National Institutes of Health (HL150234, R01DK113984, R01DK045735)