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"Importantly, our studies suggest a role for sphingolipid mediators in the regulation of prothrombotic and proinflammatory proteins in the adipose tissues in obesity. "
With the current "epidemic" of obesity that is seen as underlying, or at least aggravating, many of the health problems facing industrialized societies, increasing attention is focusing on the nature of the adipose tissue. As the role of inflammation, especially, grows in importance, it is increasingly understood that adipose tissue is not simply a mass of inert "fat" cells. According to a study published in the September 2006 issue of Diabetes, a group of lipids known as sphingolipids may play a major role in the development of the cardiovascular and metabolic diseases associated with obesity. Researchers at La Jolla Institute of Molecular Medicine the Medical University of South Carolina in Charleston believe they have identified 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 these obesity-mediated diseases.
Sphingolipids are a class of lipid that contains the organic aliphatic amino alcohol sphingosine, and all "sphingo" compounds derive their name from the Greek genitive for sphinx, because of their mysterious nature. For sphingolipids, however, it is now known that they are found in the plasma membrane, where they are believed to play a structural role, forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. They have been shown to be important bioactive mediators for a variety of cellular processes, but they have also been implicated in the pathogenesis of a range of diseases. Previous reports implicating sphingolipid metabolism in the pathogenesis of obesity/diabetes and atherosclerosis were based on investigations of sphingolipids in muscle, liver, and pancreas. In the latest study, researchers led by Fahumiya Samad, PhD, associate professor at La Jolla, examined sphingolipids in adipose tissue and in plasma.
Dr Samad and colleagues analyzed the expression and regulation of sphingolipids in the adipose tissue of genetically obese (ob/ob) mice vs that in their lean counterparts. They found that expression of 3 enzymes (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) involved in generation of ceramide (among the most simple of the sphingolipids, consisting of sphingosine plus a fatty acid) is elevated in obese adipose tissues. Significant increases in expression of all 3 enzymes were found in adipose tissues from both obese and lean mice that had been injected with insulin, although the increase in the tissue from the obese mice was "substantially greater" than that from lean mice. Significant increases in the 3 enzymes were also seen in adipose tissue after intraperitoneal injection of tumor necrosis factor-alpha (TNF-alpha) in lean mice.
These data suggest that the hyperinsulinemia and elevated TNF-alpha associated with obesity may contribute to the observed increase in the mRNA of the 3 enzymes, NSMase, ASMase, and SPT, seen in adipose tissue in this model of obesity.
Liquid chromatography/mass spectroscopy revealed a decrease in total adipose sphingomyelin and ceramide levels but an increase in sphingosine in the ob/ob mice compared with the lean mice. This "novel and unexpected" finding suggests that in obese adipose tissue, the equilibrium of sphingolipid metabolism is shifted toward generation of sphingosine, the investigators note. In contrast to the adipose tissue, plasma levels of total sphingomyelin, ceramide, sphingosine, and S1P were elevated in ob/ob mice.
Dr Samad and colleagues believe that these changes in plasma sphingolipids may be significant, because animal and human studies have shown that plasma sphingomyelin and ceramide levels are closely related to the development of atherosclerosis. "Only a fraction of the clinical complications of atherosclerosis can be explained by known risk factors," they point out.
Treatment of adipocytes cultured from mouse embryo fibroblasts with ceramide, sphingosine, and S1P was found to induce gene expression of the prothrombotic molecule plasminogen activator inhibitor-1 (PAI-1) and expression of the proinflammatory molecules TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (a functional homolog of IL-8). Dr Samad and colleagues note that these effects varied in magnitude, suggesting that they are specific effects on specific genes.
"Importantly, our studies suggest a role for sphingolipid mediators in the regulation of prothrombotic and proinflammatory proteins in the adipose tissues in obesity," they say. Despite the increasing evidence implicating the adipose tissue in contributing to obesity-related cardiovascular and metabolic risk, this is the first evidence of the molecular mechanisms that may contribute to increased adipose expression of prothrombotic and proinflammatory molecules known to be associated with these health complications.
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