Permanent activation of HMGA2 in lipomas mimics its temporal physiological activation linked to the gain of adipose tissue

Abstract

Objective: In this study the activation of HMGA2 and overexpression by FGF1-driven stimulation of adipose tissue derived stem cells (ADSCs) in adipose tissue tumors were analyzed. In addition, the expression of HMGA2 and PPAR-gamma mRNA were quantified in canine subcutaneous abdominal adipose tissue from normal and overweight purebred dogs. Design and Methods: ADSCs and adipose tissue explants stimulated with FGF1 followed by gene expression analyses of HMGA2 and p14Arf using Western-blot and qRT-PCR. Furthermore, canine subcutaneous white adipose tissue (WAT) were analyzed by qRT-PCR for their expression of HMGA2 and PPAR-gamma.Results: ADSCs and adipose tissue explants are able to execute a HMGA2 response upon FGF1 stimulation. FGF1 enhances proliferation of ADSCs by a HMGA2-dependent mechanism. In lipomas increase of HMGA2 is accompanied by increased expression of p14 Arf . Furthermore, a significantly elevated level of HMGA2 in overweight dogs and a negative correlation between the expression of HMGA2 and PPAR-gamma in subcutaneous cWAT were noted. Conclusions: These results suggest that WAT contains cells that as essential part of adipogenesis upregulate HMGA2 resulting from growth factor stimulation. In subgroups of lipoma, constitutive activation of HMGA2 due to rearrangements replaces the temporal response triggered by growth factors.

HMGA2 expression in white adipose tissue linking cellular senescence with diabetes

“…In contrast, constitutional knockout of HMGA2 is associated with a hypoplasia of WAT and a lack of an obese phenotype despite leptin deficiency (Zhou et al 1995). Accordingly, we have proposed that the temporarily strictly scheduled activation of HMGA2 distinguishes the processes in normal adult tissue from the monoclonal gain of adipose tissue underlying the development of lipomas (Thies et al 2013). However, all these results point to a pivotal role of HMGA2 in the gain of adipocytes from their precursors and stem cells, respectively.…”

“…Among the genes that have been linked to a gain of WAT and to T2D by large association studies (Ohshige et al 2011;Voight et al 2010;Zeggini et al 2007) is HMGA2 which has been linked to the development and differentiation of WAT as well. Recently, we had been able to identify an association between the expression of HMGA2 and canine obesity (Thies et al 2013). Based on these finding, we have hypothesized that the temporal activation of HMGA2 in adipose tissue stem cells is a prerequisite not only of normal turnover of adipose tissue but also of its diet-induced hyperplasia.…”

“…Moreover, even normal not immortalized cells from adult adipose tissue have been shown to be able to execute a HMGA2 response, i.e., appropriate stimuli lead to a short abundant expression of HMGA2. In a recent study, an increased ''HMGA2-response'' was found to be associated with overweight in dogs (Thies et al 2013). This challenges earlier findings that HMGA2 is a protein normally almost exclusively expressed during embryonic and fetal life.…”

Adipose-Derived Stromal Cells from Lipomas: Isolation, Characterisation and Review of the Literature

“…It has been suggested that high mobility group (HMG) proteins act as architectural factors and coordinate cell proliferation and differentiation in adult adipose tissue [36,37,46]. Research revealed that the HMGA2 gene is frequently disrupted in human solid tumours of a differentiated mesenchymal origin such as lipoma [46].…”

“…Totally, 36 articles were identified. Of those, 30 were included in the review: there were 12 case reports [1,9,10,11,26,27,28,29,30,31,32,33,34], 12 reports on basic science or animal studies [4,12,13,35,36,37,38,39,40,41,42,43,44], 2 case series [14,45] and 4 systematic reviews [13,38,46,47]. Totally, more than 60 patients were analysed; 25 articles were studied as a full-text version.…”