PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice
Takeshi Kanda, Jonathan D. Brown, Gabriela Orasanu, Silke Vogel, Frank J. Gonzalez, Juliano Sartoretto, Thomas Michel, Jorge Plutzky
Takeshi Kanda, Jonathan D. Brown, Gabriela Orasanu, Silke Vogel, Frank J. Gonzalez, Juliano Sartoretto, Thomas Michel, Jorge Plutzky
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Research Article Vascular biology

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

Abstract

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 PPARγ, a transcriptional regulator of energy balance, is expressed in endothelial cells, we set out to investigate the role of endothelial cell PPARγ in metabolism using mice that lack PPARγ in the endothelium and BM (γEC/BM-KO). When γEC/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, γEC/BM-KO mice exhibited significant dyslipidemia and failed to respond to the FFA and TG lowering effects of the PPARγ agonist rosiglitazone. BM transplantation studies, which reconstituted hematopoietic PPARγ, established that these metabolic phenotypes were due to endothelial PPARγ deficiency. We further found that the impairment in TG-rich lipoprotein metabolism in γEC/BM-KO mice was associated with fatty acid–mediated lipoprotein lipase inhibition and changes in a PPARγ-regulated endothelial cell transcriptional program. Despite their metabolic improvements, high-fat diet–fed γEC/BM-KO mice had impaired vasoreactivity. Taken together, these data suggest that PPARγ in the endothelium integrates metabolic and vascular responses and may contribute to the effects of PPARγ agonists, thus expanding what endothelial function and dysfunction may entail.

Authors

Takeshi Kanda, Jonathan D. Brown, Gabriela Orasanu, Silke Vogel, Frank J. Gonzalez, Juliano Sartoretto, Thomas Michel, Jorge Plutzky

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Figure 12

PPARγ in the endothelium integrates metabolic and vascular phenotypes.

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PPARγ in the endothelium integrates metabolic and vascular phenotypes. S...
Studies in mice lacking PPARγ in the endothelium identify endothelial PPARγ as controlling specific metabolic and vascular responses to high-fat diet, as summarized. After high-fat diet feeding, mice lacking endothelial PPARγ manifest increased plasma TG and FFA levels, decreased adiposity, less skeletal muscle TG accumulation, and decreased insulin resistance (IR). This phenotype derives from endothelial PPARγ regulation of target genes involved in TG metabolism as well as FA uptake and handling, including Cd36, aP2, CRBP-III, and Gpihbp1. In contrast, livers in endothelial PPARγ-deficient mice have greater TG accumulation, increased VLDL production, and decreased AKT phosphorylation. In the liver, the endothelium is fenestrated, which fosters FFA uptake, while in skeletal muscle and adipose tissue, a nonfenestrated endothelium is found. The dyslipidemia seen in endothelial PPARγ-deficient mice after high-fat diet and acute lipid loading involves both increased VLDL production and inhibition of LPL function by elevated FFA levels. The metabolic improvements evident in endothelial PPARγ-deficient mice contrast with their impaired arterial vasodilation, highlighting the tissue-specific actions of endothelial PPARγ, the role of the endothelium in directing metabolic responses, and the concept of metabolic endothelial function/dysfunction.