Abstract 3436: Endothelial PPARγ Regulates Lipid Metabolism And Adiposity After High Fat Feeding
Introduction: Endothelial dysfunction is common in dyslipidemia, obesity, and insulin resistance although endothelial-specific mechanisms involved in regulating metabolism have remained obscure. Peroxisome proliferator-activated receptor gamma-(PPARγ) is a transcriptional regulator of energy balance expressed in endothelial cells (EC).
Hypothesis: Endothelial PPARγ plays a role in determining metabolic status.
Methods: PPARγ-floxed mice expressing a Tie2-Cre transgene lack PPARγ in both EC and bone marrow cells (γEC/BM-KO mice). We studied the metabolic status of these mice after standard and high fat diet as well as before and after wild type PPARγ bone marrow transplantation.
Results: High fat-fed (60% kcal fat) γEC/BM-KO mice manifest significantly decreased adiposity as compared to γEC/BM-WT mice (epididymal fat depots 3.56±0.2 vs. 4.75±0.6%, n=6). Compared to controls, high fat-fed γEC/BM-KO mice had improved insulin sensitivity (glucose 128.5±9.3 vs. 181.5±12.3mg/dl; insulin 0.43±0.2 vs. 0.86±0.1ng/ml) but increased free fatty acid (FFA) and triglyceride (TG) levels. Moreover, γEC/BM-KO mice accumulated less TG in skeletal muscle and failed to develop adipocyte hypertrophy and adipose tissue growth after PPARγ agonist (rosiglitazone) treatment. γEC/BM-KO mice exhibited abnormal responses to lipid (olive oil) challenge, with increased serum FFA, TG, chylomicron and VLDL levels, and frankly lactescent plasma; these mice also failed to respond to rosiglitazone. All of these metabolic abnormalities persisted after transplantation of wild type bone marrow, identifying endothelial PPARγ as a determinant of these metabolic phenotypes. Indeed, primary microvascular EC from γ EC/BM-KO mice demonstrated significantly decreased FA uptake and an 80% reduction of CD36 mRNA expression. Impaired TG-rich lipoprotein metabolism in γ EC/BM-KO mice resulted from FA-mediated LPL inhibition.
Conclusions: Endothelial PPARγ, by playing a critical role in TG metabolism and FA handling, is a regulator of lipid metabolism, adiposity and insulin resistance, and a target involved in mediating PPARγ gonist effects. This data highlights the involvement of the endothelial organ in determining systemic metabolic responses.