Regulators of RNA m 5 C methylation are adipose tissue-specific expressed and correlate with clinical variables of obesity in humans

Stina Ingrid Svensson¹Anne Hoffmann²Akin Cayir³Sadia Saeed³Adhideb Ghosh⁴Christian Wolfrum⁴Matthias Blüher⁴Yvonne Böttcher^1*

• ¹University of Oslo, Oslo, Norway
• ²Helmholtz-Institut fur Metabolismus- Adipositas- und Gefassforschung, Leipzig, Germany
• ³Akershus Universitetssykehus HF, Lørenskog, Norway
• ⁴Eidgenossische Technische Hochschule Zurich, Zürich, Switzerland

Background: Obesity is a global health burden and recent evidence indicates that epitranscriptomic regulation is potentially involved in its etiology. The epitranscriptomic mark 5-methylcytosine (m 5 C) is implicated in cancer and recent data linked the gene expression of m 5 C writers, erasers and readers to diabetes, a well-known co-morbidity of obesity. Here, we tested whether gene expression of m 5 C regulators in paired samples of human visceral and subcutaneous adipose tissue is (i) adipose tissue depot-specific and (ii) correlates with important clinical variables of obesity.Methods: Intra-individually paired adipose tissue samples from human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) were utilizsed from three different cohorts from the Leipzig Obesity Biobank including a large cross-sectional cohort, a two-step bariatric surgery cohort and a cohort of metabolically healthy vs unhealthy individuals (LOBB, total N=962). Data analysis on intra-individual samples was performed by using the paired Wilcoxon signed-rank test, while in comparisons on independent groups the unpaired Wilcoxon rank-sum test was employed. Bonferroni correction method was used to adjust multiple testing of p-values and Spearman´s rank correlation was used to assess associations.We observed that multiple m 5 C regulators were differentially expressed between human subcutaneous and visceral adipose tissue depots. Interestingly, we found that for several regulators the effects were less pronounced after weight loss, whilst stronger in individuals with insulin resistance compared to their healthy counterparts. A strong correlation of m 5 C regulator expression with macrophages was observed in OVAT compared to its SAT counterpart. Correlations between m 5 C regulators with important clinical variables related to obesity were observed in all three cohorts.