Abstract
BackgroundInflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue.MethodsPathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject.ResultsGene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot.ConclusionsGeneration of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.
Highlights
Low grade systemic inflammation and insulin resistance often occur together, and adipose tissue is a site of inflammation in the insulin resistant state
We found greater expression of macrophagerelated genes and lower expression of adiponectin in subcutaneous adipose tissue from obese women with a high liver fat content compared to obese women with a normal liver fat content, but with comparable degrees of obesity
To investigate the basis for elevated ceramide/sphingomyelin concentrations in inflamed adipose tissue, expression levels of genes involved in ceramide synthesis and metabolism were quantified in subcutaneous adipose tissue from obese women
Summary
Low grade systemic inflammation and insulin resistance often occur together, and adipose tissue is a site of inflammation in the insulin resistant state. In adipose tissue of obese and insulin resistant subjects macrophage number and inflammatory cytokine production are increased, while adiponectin production is decreased [1]. Macrophages are often found clustered in “crown-like structures” surrounding individual adipocytes [2,3], which appear to be dead [2], suggesting that dead/ dying adipocytes may trigger macrophage influx, but the reason for adipocyte death is unknown. Another theory is that hypoxia may develop in regions of obese adipose tissue distant from the vasculature, causing hypoxic adipocytes to produce inflammatory cytokines and/or to die triggering macrophage infiltration [4]. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue
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