Altered Adipose and Plasma Sphingolipid Metabolism in Obesity

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)-␣ 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 keratinocytederived 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. Diabetes

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…Our findings are substantially in keeping with a number of previous studies in animal models and humans showing that plasma levels of ceramides are increased in obesity (Samad et al ., 2006; Haus et al ., 2009; Huang et al ., 2011). In fact, obese persons frequently have lower aerobic capacity and mitochondrial dysfunction and the cause of such dysfunction is less than clear.…”

Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes

“…Although still under debate, recent studies have also demonstrated associations with thiazide‐based treatments and increased risk of type II diabetes and subsequently increased the risk of cardiovascular events 38, 39. Phosphoethanolamines are used in the construction of sphingolipids, and perturbations in sphingolipid metabolism have been implicated in adverse cardiovascular effects, have demonstrated the ability to alter insulin resistance, and in turn may be connected to increased risk of type II diabetes 40, 41, 42. We detected a statistically significant decrease in circulating O‐phosphoethanolamine in the black group exposed to HCTZ ( q  < .05), which may be due to an increase in sphingolipid biosynthesis.…”

Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction

“…In obese rodents and humans ceramide is elevated in the liver, the hypothalamus and skeletal muscle (Adams et al, 2004;Holland et al, 2007). In leptindeficient ob/ob mice, total sphingomyelin and ceramide levels in adipose tissue are reduced, whereas circulating levels of sphingomyelin, ceramide, sphingosine and S1P are increased in plasma, since ceramide secretion by adipose tissue is increased (Samad et al, 2006). In addition, the inflammatory status associated with obesity overlaps with ceramide production.…”

“…In addition, the inflammatory status associated with obesity overlaps with ceramide production. TNF-a administration to mice results in an up-regulation of ceramide synthetic enzymes in adipose tissue, thus increasing ceramide production (Samad et al, 2006). Adiponectin, the levels of which are generally reduced in obesity and diabetes , is linked to sphingolipid metabolism.…”

“…Similarly, ceramide kinase phosphorylates ceramide to ceramide 1 phosphate (C1P) (Sugiura et al, 2002). The availability of free fatty acids and inflammatory cytokines increases ceramide synthesis (Samad et al, 2006;Schilling et al, 2013), suggesting that ceramide metabolism may be altered in obesity. In obese rodents and humans ceramide is elevated in the liver, the hypothalamus and skeletal muscle (Adams et al, 2004;Holland et al, 2007).…”