Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk

Diabetes. 2006 Sep;55(9):2579-87. doi: 10.2337/db06-0330.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / metabolism*
  • Amidohydrolases / metabolism
  • Animals
  • Ceramidases
  • Ceramides / metabolism
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL1
  • Chemokines / metabolism
  • Chemokines, CXC
  • Galactosylgalactosylglucosylceramidase / metabolism
  • Glucosyltransferases / metabolism
  • Male
  • Mice
  • Mice, Obese
  • Obesity / metabolism*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Serine C-Palmitoyltransferase / metabolism
  • Sialyltransferases / metabolism
  • Sphingolipids / blood*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelins / metabolism

Substances

  • Ccl2 protein, mouse
  • Ceramides
  • Chemokine CCL2
  • Chemokine CXCL1
  • Chemokines
  • Chemokines, CXC
  • Cxcl1 protein, mouse
  • Plasminogen Activator Inhibitor 1
  • Sphingolipids
  • Sphingomyelins
  • keratinocyte-derived chemokines
  • Serine C-Palmitoyltransferase
  • Glucosyltransferases
  • ceramide glucosyltransferase
  • Sialyltransferases
  • haematoside synthetase
  • Sphingomyelin Phosphodiesterase
  • Galactosylgalactosylglucosylceramidase
  • Amidohydrolases
  • Ceramidases