PPARgamma 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 PPARgamma, a transcriptional regulator of energy balance, is expressed in endothelial cells, we set out to investigate the role of endothelial cell PPARgamma in metabolism using mice that lack PPARgamma in the endothelium and BM (gammaEC/BM-KO). When gammaEC/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, gammaEC/BM-KO mice exhibited significant dyslipidemia and failed to respond to the FFA and TG lowering effects of the PPARgamma agonist rosiglitazone. BM transplantation studies, which reconstituted hematopoietic PPARgamma, established that these metabolic phenotypes were due to endothelial PPARgamma deficiency. We further found that the impairment in TG-rich lipoprotein metabolism in gammaEC/BM-KO mice was associated with fatty acid-mediated lipoprotein lipase inhibition and changes in a PPARgamma-regulated endothelial cell transcriptional program. Despite their metabolic improvements, high-fat diet-fed gammaEC/BM-KO mice had impaired vasoreactivity. Taken together, these data suggest that PPARgamma in the endothelium integrates metabolic and vascular responses and may contribute to the effects of PPARgamma agonists, thus expanding what endothelial function and dysfunction may entail.
Kanda
Takeshi
T
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Brown
Jonathan D
JD
Orasanu
Gabriela
G
Vogel
Silke
S
Gonzalez
Frank J
FJ
Sartoretto
Juliano
J
Michel
Thomas
T
Plutzky
Jorge
J
D000273:Adipose Tissue / Q000166:cytology / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone