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PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice
Takeshi Kanda, … , Thomas Michel, Jorge Plutzky
Takeshi Kanda, … , Thomas Michel, Jorge Plutzky
Published December 8, 2008
Citation Information: J Clin Invest. 2009;119(1):110-124. https://doi.org/10.1172/JCI36233.
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Research Article Vascular biology

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

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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 4

Tie2Cre-mediated PPARγ deletion increases serum FFA and TG levels but decreases TG deposition in skeletal muscle after high-fat diet feeding.

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Tie2Cre-mediated PPARγ deletion increases serum FFA and TG levels but de...
(A) Serum levels of adiponectin, leptin, retinol binding protein 4 (RBP4), resistin, FFA, and TG in γEC/BM-KO and γEC/BM-WT mice after standard chow or high-fat diet (n = 4–9). (B) Skeletal muscle TG content in γEC/BM-KO and γEC/BM-WT mice after high-fat diet is shown (left panel; n = 5). Western blotting and quantification of insulin-stimulated AKT serine 473 phosphorylation in skeletal muscle is shown (right panel; n = 3–6). (C) Liver TG content in γEC/BM-KO and γEC/BM-WT mice after high-fat diet is shown (left panel; n = 5). Western blotting and quantification of insulin-stimulated AKT serine 473 phosphorylation in liver is shown (right panel; n = 3–6). Real-time quantitative PCR analysis of Pparg2 and Cd36 expression in liver in γEC/BM-KO and γEC/BM-WT mice after high-fat diet (n = 5). *P < 0.05, **P < 0.01 versus obese γEC/BM-WT mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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