HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

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.

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…A mechanistic role of inflammasome activation in determining aerobic capacity (measured by peak oxygen uptake) was suggested since the percentage of methylation of the ASC gene and plasma IL-1β levels correlated with aerobic capacity in stable outpatients with heart failure [191]. Also, response to hypoxia in adipocytes was related to gene promoter hypomethylation and up-regulation of proinflammatory cytokines [192]. Moreover, gestational intermittent hypoxia induced endothelial dysfunction, triggered pro-inflammatory gene expression, and caused epigenetic changes in adult male offspring to increase the risk of developing cardiometabolic disease [193].…”

Adipose Tissue Hypoxia Correlates with Adipokine Hypomethylation and Vascular Dysfunction

“…The current study's findings indicate a direct association between VAT hypoxia and elevated TET1 protein and adipokine hypomethylation levels, implying that TET1 plays a role in the regulation of hypoxia-induced inflammation. This role was demonstrated mechanistically in our prior investigations, which showed an increase in HIF1α and TET1 protein levels and decreased global and gene-specific DNA methylation in adipocytes cultured under hypoxic conditions [16]. Together, our previous mechanistic findings in adipocytes along with the current correlation observed between HIF1α and TET1 in the adipose tissue suggest that obesity-related production of inflammatory cytokines could be mediated by an epigenetic process that is sensitive to changes in the adipose tissue microenvironment, specifically oxygen levels.…”

“…The role of TET1 has been recently explored in cancer and developmental diseases; however, there is an apparent lack in studying this mechanism in the context of obesity and vascular dysfunction [15]. We previously reported on the role of the HIF1α-inducible TET1 enzyme in causing hypomethylation and inducing mRNA expression of several adipokines in cultured adipocytes [16]. The current study will test this concept in adipose tissue samples obtained from obese and non-obese subjects.…”

Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation

“…When specifically looking for effects of Tet1, we found that the activities of Myc, Rest and Rreb1 were consistently reduced when Tet1 was lost in AT2 cells regardless of HDM status (Figure 7C). Hif1α, whose expression is regulated by Tet1 77 and may also regulate Tet1 expression 78 , showed reduced activity in KO-Saline (Figure 7D). Increased Foxa1 activity was only observed in KO-HDM compared to WT-HDM (Figure 7E).…”