Abstract
Hypoxia in adipose tissue is suggested to be involved in the development of a chronic mild inflammation, which in obesity can further lead to insulin resistance. The effect of hypoxia on gene expression in adipocytes appears to play a central role in this inflammatory response observed in obesity. However, the global impact of hypoxia on transcriptional changes in human adipocytes is unclear. Therefore, we compared gene expression profiles of human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes under normoxic or hypoxic conditions to detect hypoxia-responsive genes in adipocytes by using whole human genome microarrays. Microarray analysis showed more than 500 significantly differentially regulated mRNAs after incubation of the cells under low oxygen levels. To gain further insight into the biological processes, hypoxia-regulated genes after 16 hours of hypoxia were classified according to their function. We identified an enrichment of genes involved in important biological processes such as glycolysis, response to hypoxia, regulation of cellular component movement, response to nutrient levels, regulation of cell migration, and transcription regulator activity. Real-time PCR confirmed eight genes to be consistently upregulated in response to 3, 6 and 16 hours of hypoxia. For adipocytes the hypoxia-induced regulation of these genes is shown here for the first time. Moreover in six of these eight genes we identified HIF response elements in the proximal promoters, specific for the HIF transcription factor family members HIF1A and HIF2A. In the present study, we demonstrated that hypoxia has an extensive effect on gene expression of SGBS adipocytes. In addition, the identified hypoxia-regulated genes are likely involved in the regulation of obesity, the incidence of type 2 diabetes, and the metabolic syndrome.
Highlights
White adipose tissue is a major endocrine organ and secretes various bioactive proteins – the adipokines – which are involved in different physiological processes [1,2,3]
The analyzed genes are involved in several biological processes, and significance of enrichment was evaluated for glycolysis (10 genes), response to hypoxia (16 genes), regulation of cellular component movement (17 genes), response to nutrient levels (16 genes), regulation of cell migration (13 genes) and transcription regulator activity (60 genes)
The result was filtered according to their p-values (,0.007) and Yes/No ratio (.1.3) and ranked according to their Yes/No ratio which represents their abundance in the set of 9 genes (ADM, ankyrin repeat domain 37 (ANKRD37), damage-inducible transcript 4 (DDIT4), KDM3A, PFKFB4, PPP1R3C, vascular endothelial growth factor A (VEGFA), WD-repeat domain 73 (WDR73) and zink finger protein 395 (ZNF395)) compared to the background
Summary
White adipose tissue is a major endocrine organ and secretes various bioactive proteins – the adipokines – which are involved in different physiological processes [1,2,3]. Adipose tissue hypoxia was suggested to be involved in the dysregulation of adipokine expression and in the consequential development of obesity-related insulin resistance and chronic inflammation [4,5]. This hypothesis was recently confirmed when evidence was provided that hypoxia occurs in the adipose tissue of different obese mouse models and that hypoxia contributes to the endocrine dysregulations [6,7,8]. Adipose tissue undergoes expansion and growth and remodelling of its capillary network is required [11]
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