Fatty Acid Induced Hypermethylation in the <i>Slc2a4</i> Gene in Visceral Adipose Tissue Is Associated to Insulin-Resistance and Obesity

Fatty Acid Induced Hypermethylation in the <i>Slc2a4</i> Gene in Visceral Adipose Tissue Is Associated to Insulin-Resistance and Obesity

De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by <i>Slc2a4</i>). <i>Slc2a4</i> expression, ChREBP activity, and DNL are decr...

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Bibliographic Details
Main Authors: Jan H. Britsemmer, Christin Krause, Natalie Taege, Cathleen Geißler, Nuria Lopez-Alcantara, Linda Schmidtke, Alison-Michelle Naujack, Jonas Wagner, Stefan Wolter, Oliver Mann, Henriette Kirchner
Format: Article
Language:English
Published: MDPI AG 2023-03-01
Series:International Journal of Molecular Sciences
Subjects:
<i>Slc2a4</i>
DNA methylation
human visceral adipose tissue
insulin resistance
diet-induced obese mice
Online Access:https://www.mdpi.com/1422-0067/24/7/6417
Description
Summary:De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by <i>Slc2a4</i>). <i>Slc2a4</i> expression, ChREBP activity, and DNL are decreased in obesity, the underlying cause however remains unidentified. We hypothesize that increased DNA methylation in an enhancer region of <i>Slc2a4</i> decreases <i>Slc2a4</i> expression in obesity and insulin resistance. We found that <i>SLC2A4</i> expression in VAT of morbidly obese subjects with high HbA1c (>6.5%, <i>n</i> = 35) is decreased, whereas DNA methylation is concomitantly increased compared to morbidly obese subjects with low HbA1c (≤6.5%, <i>n</i> = 65). In diet-induced obese (DIO) mice, DNA methylation of <i>Slc2a4</i> persistently increases with the onset of obesity and insulin resistance, while gene expression progressively decreases. The regulatory impact of DNA methylation in the investigated enhancer region on SLC2A4 gene expression was validated with a reporter gene assay. Additionally, treatment of 3T3 pre-adipocytes with palmitate/oleate during differentiation decreased DNA methylation and increased <i>Slc2a4</i> expression. These findings highlight a potential regulation of <i>Slc2a4</i> by DNA methylation in VAT, which is induced by fatty acids and may play a role in the progression of obesity and insulin resistance in humans.
ISSN:1661-6596
1422-0067

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