Adipose Tissue Hypoxia Correlates with Adipokine Hypomethylation and Vascular Dysfunction

Abstract

Obesity is characterized by the accumulation of dysfunctional adipose tissues, which predisposes to cardiometabolic diseases. Our previous in vitro studies demonstrated a role of hypoxia in inducing adipokine hypomethylation in adipocytes. We sought to examine this mechanism in visceral adipose tissues (VATs) from obese individuals and its correlation with cardiometabolic risk factors. We propose an involvement of the hypoxia-inducible factor, HIF1α, and the DNA hydroxymethylase, TET1. Blood samples and VAT biopsies were obtained from obese and non-obese subjects (n = 60 each) having bariatric and elective surgeries, respectively. The analyses of VAT showed lower vascularity, and higher levels of HIF1α and TET1 proteins in the obese subjects than controls. Global hypomethylation and hydroxymethylation were observed in VAT from obese subjects along with promoter hypomethylation of several pro-inflammatory adipokines. TET1 protein was enriched near the promotor of the hypomethylated adipokines. The average levels of adipokine methylation correlated positively with vascularity and arteriolar vasoreactivity and negatively with protein levels of HIF1α and TET1 in corresponding VAT samples, serum and tissue inflammatory markers, and other cardiometabolic risk factors. These findings suggest a role for adipose tissue hypoxia in causing epigenetic alterations, which could explain the increased production of adipocytokines and ultimately, vascular dysfunction in obesity.

An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions

“…On top of these genes is HIF3A (hypoxia-inducible factor 3a), which is an essential gene in metabolic and physiological responses to hypoxia whose methylation has been linked to obesity in both adults and children [25,26]. In addition, genes involved in inflammation and oxidative stress such as TNF (tumor necrosis factor), IL6 (interleukin 6), and TFAM (mitochondrial transcription factor A) exhibited aberrant DNA methylation in obese individuals and correlated with abnormal expression and disturbed function of these genes [27][28][29]. Collectively, obesity has been linked to altered DNA methylation patterns, which could serve as biomarkers and therapeutic targets.…”

“…Collectively, obesity has been linked to altered DNA methylation patterns, which could serve as biomarkers and therapeutic targets. These changes have been linked to a disrupted balance between DNA methyltransferases (DNMTs) and active demethylases such as TETs (Ten-eleven translocation methylcytosine dioxygenase 1) [28][29][30][31]. However, further research is needed to identify the underlying mechanisms of aberrant DNA methylation in obesity.…”

CD147 Levels in Blood and Adipose Tissues Correlate with Vascular Dysfunction in Obese Diabetic Adults

“…Nitrate and nitrite, stable NO metabolites, were quantified in plasma samples using the Griess-based reaction kit purchased from Cayman Chemicals (Ann Arbor, MI, USA), following our previously published protocol [17][18][19]. Briefly, samples were ultra-filtered via Millipore centrifugal filters with a cut-off molecular weight of 10 KDa (Burlington, MA, USA).…”

“…All waveforms were detected on the right side of the body with applanation tonometry (SphygmoCor; AtCor Medical, Sydney, Australia). This approach is described in detail in previous publications by our research group [17][18][19][20].…”

“…Adipose tissue samples were dissected, and resistance arterioles were isolated then prepared for flow-induced dilation (FID) measurements in response to a gradual increase in intraluminal pressure gradient as we previously reported [17][18][19][21][22][23][24]. Briefly, the dissected arterioles were cannulated via glass micropipettes in an organ perfusion chamber and visualized by video microscopy.…”