Altered Adipose and Plasma Sphingolipid Metabolism in Obesity

A Potential Mechanism for Cardiovascular and Metabolic Risk

  1. Fahumiya Samad1,
  2. Kelly D. Hester1,
  3. Guang Yang1,
  4. Yusuf A. Hannun2 and
  5. Jacek Bielawski2
  1. 1Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, California
  2. 2Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
  1. Address correspondence and reprint requests to Dr. Fahumiya Samad, Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121. E-mail: fsamad{at}ljimm.org

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)-α 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-α, 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 13, 2006.
    • Received March 13, 2006.
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