Abstract
The architectural transcription factor high-mobility group AT-hook 1 (HMGA1) is a chromatin regulator with implications in several biological processes, including tumorigenesis, inflammation, and metabolism. Previous studies have indicated a role for this factor in promoting the early stages of adipogenesis, while inhibiting adipocyte terminal differentiation, and decreasing fat mass. It has been demonstrated that hypoxia – through the hypoxia-inducible factor 1 (HIF-1) – plays a major role in triggering changes in the adipose tissue of the obese, leading to inhibition of adipocyte differentiation, adipose cell dysfunction, inflammation, insulin resistance, and type 2 diabetes. To examine the possible cooperation between HMGA1 and HIF-1, herein, we investigated the role of HMGA1 in the regulation of Visfatin and VEGF, two genes normally expressed in adipose cells, which are both responsive to hypoxia. We demonstrated that HMGA1 enhanced Visfatin and VEGF gene expression in human embryonic kidney (HEK) 293 cells in hypoxic conditions, whereas HMGA1 knockdown in differentiated 3T3-L1 adipocytes reduced these effects. Reporter gene analysis showed that Visfatin and VEGF transcriptional activity was increased by the addition of either HMGA1 or HIF-1 and even further by the combination of both factors. As demonstrated by chromatin immunoprecipitation in intact cells, HMGA1 directly interacted with the VEGF gene, and this interaction was enhanced in hypoxic conditions. Furthermore, as indicated by co-immunoprecipitation studies, HMGA1 and HIF-1 physically interacted with each other, supporting the notion that this association may corroborate a functional link between these factors. Therefore, our findings provide evidence for molecular cross-talk between HMGA1 and HIF-1, and this may be important for elucidating protein and gene networks relevant to obesity.
Highlights
Obesity is a pathological condition often associated with insulin resistance, type 2 diabetes, cardiovascular disease, and even certain types of cancers [1, 2]
To test the hypothesis that HMGA1 could play a functional role in the transcriptional regulation of genes activated in hypoxic conditions, we first examined two genes, vascular endothelial growth factor (VEGF) and Visfatin, which are both naturally expressed in adipose cells, and regulated by hypoxia
We tested Visfatin and VEGF gene expression, and their response to hypoxia, in murine differentiated 3T3-L1 adipocytes, which express high levels of HMGA1 protein, and in human human embryonic kidney (HEK)-293 cells, a cell line ideally suited for studying the effects of HMGA1 on transcription since it does not express appreciable amounts of HMGA1
Summary
Obesity is a pathological condition often associated with insulin resistance, type 2 diabetes, cardiovascular disease, and even certain types of cancers [1, 2]. A major, relatively recent advancement in this field has been the concept that adipose tissue is not just an inert reserve of lipids, but a source of biomolecules, collectively called adipocytokines, with important implications in insulin sensitivity, inflammation, and angiogenesis [3,4,5]. As adipocytokines are differentially expressed in the adipose tissue of obese versus lean individuals, a pro-inflammatory, insulin resistant, pro-atherogenic pattern typically prevails in the obese state. It has been recognized that, in obesity, hypertrophic adipocytes produce monocyte chemotactic protein-1 (MCP-1), a factor favoring the infiltration of macrophages into fat tissue, while these immune cells produce pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), which sustain, in turn, adipose cell dysfunction [6, 7]. The initial events leading to these changes in adipose tissue are still poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
