PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice

Although endothelial dysfunction, defined as abnormal vasoreactivity, is a common early finding in individuals with type 2 diabetes, the endothelium has not been known to regulate metabolism. As PPAR gamma, a transcriptional regulator of energy balance, is expressed in endothelial cells, we set out to investigate the role of endothelial cell PPAR gamma in metabolism using mice that lack PPAR gamma in the endothelium and BM (gamma EC/BM-KO). When gamma EC/BM-KO mice were fed a high-fat diet, they had decreased adiposity and increased insulin sensitivity compared with control mice, despite increased serum FFA and triglyceride (TG) levels. After fasting or olive oil gavage, gamma EC/BM-KO mice exhibited significant dyslipidemia and failed to respond to the FFA and TG lowering effects of the PPAR gamma agonist rosiglitazone. BM transplantation studies, which reconstituted hematopoietic PPAR gamma, established that these metabolic phenotypes were due to endothelial PPAR gamma deficiency. We further found that the impairment in TG-rich lipoprotein metabolism in gamma EC/BM-KO mice was associated with fatty acid-mediated lipoprotein lipase inhibition and changes in a PPAR gamma-regulated endothelial cell transcriptional program. Despite their metabolic improvements, high-fat diet-fed gamma EC/BM-KO mice had impaired vasoreactivity. Taken together, these data suggest that PPAR gamma in the endothelium integrates metabolic and vascular responses and may contribute to the effects of PPAR gamma agonists, thus expanding what endothelial function and dysfunction may entail.