Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk.
The adipose tissue has become a central focus in the pathogenesis of obesity-mediated cardiovascular and metabolic disease. Here we demonstrate that adipose sphingolipid metabolism is altered in genetically obese (ob/ob) mice. Expression of enzymes involved in ceramide generation (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) and ceramide hydrolysis (ceramidase) are elevated in obese adipose tissues. Our data also suggest that hyperinsulinemia and elevated tumor necrosis factor (TNF)-alpha associated with obesity may contribute to the observed increase in adipose NSMase, ASMase, and SPT mRNA in this murine model of obesity. Liquid chromatography/mass spectroscopy revealed a decrease in total adipose sphingomyelin and ceramide levels but an increase in sphingosine in ob/ob mice compared with lean mice. In contrast to the adipose tissue, plasma levels of total sphingomyelin, ceramide, sphingosine, and sphingosine 1-phosphate (S1P) were elevated in ob/ob mice. In cultured adipocytes, ceramide, sphingosine, and S1P induced gene expression of plasminogen activator inhibitor-1, TNF-alpha, monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine. Collectively, our results identify a novel role for sphingolipids in contributing to the prothrombotic and proinflammatory phenotype of the obese adipose tissue currently believed to play a major role in the pathogenesis of obesity-mediated cardiovascular and metabolic disease.
Samad
Fahumiya
F
Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121, USA. fsamad@ljimm.org
Hester
Kelly D
KD
Yang
Guang
G
Hannun
Yusuf A
YA
Bielawski
Jacek
J
D000273:Adipose Tissue / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D055572:Ceramidases; D002518:Ceramides / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D054360:Chemokine CXCL1; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC; D002517:Galactosylgalactosylglucosylceramidase / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D012799:Sialyltransferases / Q000378:metabolism; D013107:Sphingolipids / Q000097:blood*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism
C491768:Ccl2 protein, mouse; D002518:Ceramides; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D013107:Sphingolipids; D013109:Sphingomyelins; C074302:keratinocyte-derived chemokines; D051102:Serine C-Palmitoyltransferase; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D012799:Sialyltransferases; C021343:haematoside synthetase; D013108:Sphingomyelin Phosphodiesterase; D002517:Galactosylgalactosylglucosylceramidase; D000581:Amidohydrolases; D055572:Ceramidases