HOX gene network is involved in the transcriptional regulation of in vivo human adipogenesis

Abstract

Adipogenesis is regulated by the sequential activation of a series of transcription factors: the C/EBP proteins of type beta and delta trigger the process while PPARgamma and C/EBPalpha induce the differentiation from pre-adipocyte to adipocyte, followed by adipo-specific gene expression. A number of observations suggest the involvement of genes controlling embryonal development in adipogenesis. In human thyroid follicular carcinoma, it has been recently identified an oncogenetic fusion protein resulting from the interaction between the isoform PPARgamma1 of PPARgamma and the homeoprotein encoded by the PAX-8 gene. Recent observations have pointed out that gene expression associated with adipocyte differentiation in vivo and in vitro, although partially overlapping, is actually different. HOX genes make up a network of transcription factors (homeoproteins) controlling embryonal development as well as crucial functions of adult eukaryotic cells. The molecular organization of this network of 39 genes appears to be unique in the genome and probably acts regulating phenotypic cell identity. In the present study we have analyzed the expression of the complete HOX gene network, in vivo, in different deposits of human white adipose tissue and in embryonal brown adipose tissues. Most of the genes in the HOX network are active in white as well as brown adipose tissue. Furthermore HOX genes display a deposit-specific expression in white adipose tissue. Moreover, expression of the paralogous group 4 genes (HOX A4, HOX B4, HOX C4, and HOX D4), together with that of isolated genes in the network, appears to discriminate between white and brown adipose tissue. This data allows us to postulate the involvement of the HOX network in transcriptional regulation of human adipogenesis and to hypothesize on the molecular mechanisms that could be implicated.

Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration

“…Indeed, intraabdominal/visceral fat accumulation is associated with a higher risk of diabetes and metabolic syndrome, whereas increased s.c. fat in the thighs and hips may even have a protective effect (4,8,26). A growing body of evidence suggests that these depot-specific associations are due to intrinsic differences in the properties of adipocytes in each depot (27,28) and the consequence of a divergence in their developmental origin (1,(9)(10)(11)(12)29). Consistent with this hypothesis, we and others observed high differential expression of developmental genes between intraabdominal and s.c. adipose depots in both rodents and humans (11,12).…”

“…Recently, we and others have shown that several developmental genes, including several Hox genes, Shox2, Engrailed-1, and Tbx15, are differentially expressed between intraabdominal and s.c. adipocytes and preadipocytes of rodents and humans, in many cases by several orders of magnitude (9)(10)(11)(12). We hypothesized that these genes may play a role in adipose depot development and ultimately in differential adipose depot function.…”

Differentiation and characterization of human facial subcutaneous adipocytes

“…Despite that none has previously attempted to isolate and characterize facial preadipocytes, many others have identified depot specific HOX genes expression pattern in different adipose sites, [26][27][28] , suggesting their potential function driving a distinct depot characteristics. The HOX network are transcriptional factors, comprised of 39 genes regulating developmental process during embryogenesis, but also plays an important role in metabolic, somatic and congenital functions in adults.…”

Hyperexpression of locus C genes in the HOX network is strongly associated in vivo with human bladder transitional cell carcinomas

“…The HOX gene network, the most repeat-poor regions of the human genome (Lander et al, 2001), is also expressed in normal adult human organs (Cillo, 1994-95). Hox and homeobox genes appear to regulate normal development, cell differentiation (Magli et al, 1991;Cantile et al, 2003b) and control other cellular processes, as proven by the recent description of congenital (Mortlock and Innis, 1997), somatic (Nakamura et al, 1996), metabolic (Ferber et al, 2000) and neoplastic alterations (Gromova et al, 1999;Cillo et al, 2001;Abate-Shen, 2002) involving these genes.…”