Biological Determinants of Metabolic Syndrome in Visceral and Subcutaneous Adipose Tissue from Severely Obese Women

Abstract

The metabolic syndrome (MetS) is a cluster of the most dangerous heart attack risk factors: diabetes or raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. The goal of this study is to compare the state of the main features of obesity-associated white adipose tissue (WAT) dysfunction in 66 women with severe obesity without (MetS-) or with MetS (MetS+). Fat cell area, adipocyte size distribution and histological fibrosis were analysed in visceral (VAT) and abdominal subcutaneous WAT (SAT) in 33 age- and BMI-matched pairs of MetS- and MetS+ subjects. The mRNA expression of 93 genes implicated in obesity-associated WAT dysfunction was analysed by RT-qPCR in both fat depots. MetS+ females showed higher adipocyte hypertrophy in both fat depots and increased fibrosis and expression of macrophage and hypoxia markers in SAT. Transcriptional data suggest increased fatty acid oxidation in SAT and impaired thermogenesis and extracellular matrix remodelling in VAT from MetS+ subjects. A sPLS-DA model, including SAT expression of PPARA and LEPR genes identified MetS with an AUC = 0.87. Despite equal age, BMI and body composition, MetS+ females display morphological and transcriptional differences in both WAT depots, especially in SAT. These factors may contribute to the transition to MetS.

Keywords: metabolic syndrome; obesity; subcutaneous adipose tissue; visceral adipose tissue.

Figure 1

Fat cell size distribution and fibrosis. Comparison of adipocyte cell surface area and representative images (A) of SAT and VAT samples from MetS− and MetS+ individuals. Frequency distribution analysis of fat cell areas divided by size into bin intervals of 200 µm² and into three representative sizes (B). Data are presented as the average ± SD frequencies of cells within each bin and compared by the Holm–Sidak t-test for multiple comparisons or by Welch’s t-test among size intervals. Comparison of histological pericellular fibrosis and representative images (C). Data are presented as the ratio of fibrous tissue area stained with picrosirius red/total tissue surface. SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; MetS−, severely obese without MetS; MetS+, severely obese with MetS. * = p < 0.05.

Figure 2

Subcutaneous and visceral fat gene expression signature model for MetS. (A) sPLSDA receiver operating characteristic (ROC) analysis of the gene expression signature components. Lines correspond to the accuracy classification performance of each component, including the previous. (B) sPLSDA loading plot. Bar length corresponds to each gene loading weight (importance) into the model. Bar color indicates the group in which the mean gene expression is higher. (C) Gene expression hierarchical dendrogram heatmap of the transcriptome signature. Euclidean distance metric with Ward’s group linkage algorithm was performed to cluster groups. MetS−, severely obese without MetS; MetS+, severely obese with MetS.