Human adipocytes from the subcutaneous superficial layer have greater adipogenic potential and lower PPAR-γ DNA methylation levels than deep layer adipocytes

Abstract

Human subcutaneous fat tissue consists of two layers, superficial adipose tissue (SAT) and deep adipose tissue (DAT). Some recent reports suggest that a disproportionate accumulation of DAT is related to obesity-associated metabolic complications. However, the differences in adipocyte function between SAT and DAT are unclear. To clarify the differences in human adipocyte characteristics between SAT and DAT, human ceiling culture-derived proliferative adipocytes (ccdPAs) were primary cultured from SAT and DAT of three lean female patients. Differences in adipogenic differentiation potential and sensitivity to exogenous adipogenic factors were examined. Epigenetic modification of the CpG island DNA methylation levels of genes related to adipogenesis was measured. In histological analyses, the mean adipocyte size in SAT was significantly larger than that in DAT (8,741 ± 416 vs. 7,732 ± 213 μm(2), P < 0.05). Primary cultured adipocytes from SAT showed significantly greater adipogenesis than did those of DAT. Sensitivity to partial adipogenic stimulation was significantly different between ccdPAs of SAT and DAT. Peroxisome proliferator-activated receptor-γ (PPAR-γ) protein expression and leptin protein secretion from ccdPAs were significantly higher in SAT than DAT. DNA methylation levels of PPAR-γ were significantly lower in ccdPAs of SAT than DAT. Adipocyte size was larger in SAT than DAT in vivo. This is consistent with the findings of an in vitro study that, compared with ccdPAs in DAT, ccdPAs in SAT have higher adipogenic potential and lower DNA methylation levels of PPAR-γ.

The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function

“…It has been demonstrated that deep abdominal subcutaneous adipose tissue has a higher expression of pro-inflammatory, lipogenic and lipolytic genes, and contains higher proportions of saturated fatty acids and an increased proportion of small adipocytes [33,34]. The latter finding is in line with greater adipogenic potential and lower PPAR-γ DNA methylation levels in abdominal superficial as compared to deep-layer adipocytes [35]. Moreover, deep abdominal subcutaneous adipose tissue seems to expand disproportionally more than the superficial fat depot with increasing obesity, which predisposed toward whole-body insulin resistance and increased cardiovascular risk independent of other adiposity measures in men [34].…”

A novel conjunctive microenvironment derived from human subcutaneous adipose tissue contributes to physiology of its superficial layer

“…We found a significantly greater area of intracytoplasmic lipid accumulation in ASCs induced to adipogenic lineage from the sSAT microenvironment together with the highest number of unilocular cells. Kosaka and collaborators showed that adipocytes from the sSAT occupy a greater area compared with the dSAT, besides having a higher quantity of these cells [ 12 ]. Previous studies have shown a higher adipogenic potential from sSAT compared with dSAT isolated from obese samples [ 11 , 13 , 30 ].…”

“…Recently, Lee and collaborators described a significant correlation between serum levels of inflammatory cytokines and adipokines with the sum of dSAT area [ 10 ]. On the other hand, two independent studies [ 11 , 12 ] revealed a higher adipogenic potential for adipocyte progenitor cells isolated from the superficial SAT (sSAT). Furthermore, gene expression analysis revealed several metabolic and anti-inflammatory genes, including adiponectin preferentially expressed in sSAT, whereas inflammatory genes are over-expressed in dSAT in human obese samples [ 13 ].…”

Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications

“…However, decreased PPARg expression via modifications of epigenetic mechanisms may play a pivotal role in the development of obesity and diabetes (29-33, 35, 36). Few studies have shown that DNA methylation and histone modifications regulate the expression of PPARg in WAT (32,(35)(36)(37)(38)(39). First, during adipogenesis, DNA demethylation (32), as well as enrichment of active marks H3ac (40) and H3K4me3 (41,42), was observed in the PPARg promoter region that positively regulates gene expression.…”