Adipose tissue is considered as the largest endocrine organ in humans, and includes numerous discrete anatomical depots. There is evidence that different adipose tissue depots have different morphology, physiology and adipokine profiles. Although depot differences in adipocyte metabolism and endocrine function are clearly important in etiology of obesity related diseases, the relative contribution of VAT compared to abdominal subcutaneous is still controversial. Moreover, there is little evidence of in vivo or in vitro differences between different subcutaneous adipose depot.
The advent of new technology that allows the characterization of entire transcriptomes has permitted to look from another perspective to adipose tissue depots heterogeneity and led to the hope that the properties of adipose tissue and differences between adipose tissue depots might be revealed to help discover new therapeutic avenues.
Indeed, expression profiling has revealed significant differences in expression of hundreds of genes between different depots of adipose tissue in both rodents and humans [28–30], particularly developmental and patterning genes involved in cell differentiation, organogenesis, antero-posterior or dorso-ventral patterning. These findings not only have contributed to help explain the distinct impact of these depots on the development of metabolic complications but also have suggested possible differences in developmental origin of these fat cells [31].
Adipose tissue has a mesodermal origin. A layer of cells between the primitive endoderm and ectoderm migrates and spreads along the antero-posterior and dorso-ventral axes of the developing embryo generating the axial, intermediate, lateral plate, and paraxial mesoderm. Each of these embryologic tissues eventually gives rise to local adipose tissue. Vertebrate embryonic patterning and evolution of mesodermal tissues such as fat are controlled by several conserved developmental signaling systems. The mesenchimal stem cell gives origin to an early precursor, the adipoblast, which develops into committed preadipocytes that under appropriate stimuli differentiate into mature adipocytes of different types.
In more recent studies, the differences in gene expression pattern have been shown to persist even after in vitro differentiation of preadipocytes, suggesting that the differences are independent of extrinsic factors and that different adipocyte progenitors are programmed through epigenetic modulation during early development, participating in determining functional differences observed between different adipose tissue depots [27].
The most frequently observed differences in gene expression involve HOX genes, a subset of Homeobox genes. A Homeobox is a DNA sequence, around 180 base pairs long, found within genes that are involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi and plants. These genes encode Homeodomain protein products that are transcription factors sharing a characteristic protein fold structure that binds DNA. Through the DNA-recognition properties of the Homeodomain, Homeoproteins are believed to regulate the expression of targeted genes and direct the formation of many body structures during early embryonic development. Many Homeodomain proteins induce cellular differentiation by initiating the cascades of coregulated genes required to produce individual tissues and organs. Thus, Homeobox genes are critical in the establishment of body axes during embryogenesis. The HOX genes in humans are organized in four chromosomal clusters: HOXA, HOXB, HOXC and HOXD.
In a 2006 study from Gesta et al., gene expression profiling has revealed that intraabdominal (visceral) adipocytes express higher levels of HOXA5, HOXA4, HOXC8 and NR2F1, whereas subcutaneous fat has higher levels of HOXA10, and HOXC9, and in most cases, these differences are observed in both rodents and humans. Similar differences in development gene expression are observed in preadipocytes isolated from different adipose depots of rodents. These differences in gene expression are large in magnitude (up to 1000-fold), appear to be intrinsic, and persist during in vitro culture and differentiation, indicating that they are cell autonomous and independent of the tissue microenvironment. In addition, the authors have shown that one of these developmental genes (HOXA5) exhibit changes in expression that closely correlate with the extent of obesity (BMI) and the pattern of fat distribution (WHR).
In recent study from Karastergiou et al. substantial differences in HOX genes expression have been found between two different subcutaneous adipose tissue depots, gluteal and abdominal. In our study, we confirm significant gene expression differences between abdominal and gluteal SAT, as well seen in the hierarchical clustering analysis. We underline differences in expression of developmental and patterning genes such as HOX genes (HOXA3, HOXA5, HOXB7, HOXB8, HOXA11, HOXA13, HOXC10, HOXC12), as previously observed.
We have also noticed as some genes, that in previous studies have been proposed as moleculare signatures of VAT, such as HOXA5 and NR2F1 appear to be up-regulated in abdominal compared to gluteal SAT (g-SAT), suggesting a similarity between VAT and abdominal SAT (a-SAT).
Furthermore, the finding that a consistent number of genes differentially expressed between gluteal and abdominal adipose depots have been previously correlated to pathogenesys of type 2 diabetes enforces our hypotesis that these depots may have a different impact in obesity associated metabolic complications.