Abstract
Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.
Highlights
Obesity is a common and serious disease that affects more than one third (36.5%) of U.S adults and over 600 million adults worldwide [1]
The main findings are that (1) gene expression of leptin and inflammatory cytokines was induced in adipocytes cultured under hypoxic conditions; (2) this response was mediated by DNA hypomethylation in the corresponding gene promoters; (3) HIF1α and the DNA hydroxymethylase ten-eleven translocation-1 (TET1) contributed, at least in part, to the hypoxia-induced gene promoter hypomethylation
We explored the role of TET1 enzyme in hypoxia-induced hypomethylation using primary adipocytes, hoping to reveal the mechanism by which dysfunctional adipose tissues produce excess inflammatory cytokines in obesity and comorbidities
Summary
Obesity is a common and serious disease that affects more than one third (36.5%) of U.S adults and over 600 million adults worldwide [1]. Unlocking the complicated interplay between obesity and its co-morbidities by investigating the changes it causes in gene expression is extremely significant. Obesity is associated with hypoxia in adipose tissues [4]. Our current hypothesis is that hypoxia in adipose tissues triggers changes in the DNA methylation profile in adipocytes. Aberrant DNA hyper- or hypomethylation can result in unscheduled gene overexpression. Aberrant DNA methylation can be induced by changes in the surrounding microenvironment such as oxygen levels [5]. It has been shown that DNA hypomethylation in cancer can be induced via active demethylation by the hydroxy methylase enzymes, TETs [8,9]. We hypothesize that DNA hypomethylation that accompanies hypoxia may occur secondary to an increased expression of the HIF-1α-inducible
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