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.
Highlights
Obesity is a considerable public health issue that affects more than one-third (36.5%)of the US population and over 600 million adults worldwide [1]
We previously reported on the role of the hypoxia-inducible factor 1 alpha (HIF1α)-inducible Ten-eleven translocation methylcytosine dioxygenase (TET1) enzyme in causing hypomethylation and inducing mRNA
Total body fat and visceral adipose tissues (VAT) percentages measured via dual-energy X-ray absorptiometry (DEXA) scanning were significantly higher in obese subjects than non-obese controls (p < 0.0001)
Summary
Obesity is a considerable public health issue that affects more than one-third (36.5%)of the US population and over 600 million adults worldwide [1]. Obesity is associated with many life-threatening yet preventable comorbidities, such as cardiovascular (CVD), diabetes, and cancer [2]. Obesity is characterized by a vast accumulation of dysfunctional adipose tissue, and currently, it is largely accepted that these fat depots represent key secretory organs that release multiple bioactive molecules, hormones, and inflammatory cytokines [3]. Obesity is associated with hypoxia, especially in the expanding adipose tissues, as shown in previous clinical and preclinical studies [4]. It was postulated over a decade ago that adipose tissues could become hypoxic due to obesity-induced adipose accumulation. Several studies in obese mice have shown that severe adiposity can cause
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