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Altered Adipose and Plasma Sphingolipid Metabolism in Obesity

A Potential Mechanism for Cardiovascular and Metabolic Risk

¹ Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, California
² Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina

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

Abbreviations: ASMase, acid sphingomyelinase; GM3, N-acetylneuraminylgalactosylceramide; HPLC, high-performance liquid chromatography; IL, interleukin; KC, keratinocyte-derived chemokine; MCP-1, monocyte chemoattractant protein-1; NSMase, neutral sphingomyelinase; PAI-1, plasminogen activator inhibitor-1; S1P, sphingosine 1-phosphate; SPT, serine palmitoyl transferase; TMS, tandem mass spectrometry; TNF-, tumor necrosis factor-

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)- 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-, 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.

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