Stina Ingrid Alice Svensson

• Svensson, Stina Ingrid Alice; Hoffmann, Anne; Hagemann, Tobias; Cayir, Akin; Saeed, Sadia & Ghosh, Adhideb [Show all 9 contributors for this article] (2025). Regulators of RNA m5C methylation are adipose tissue depot-specific expressed and correlate with clinical variables of obesity in humans. Frontiers in Endocrinology. 16. doi: 10.3389/fendo.2025.1647477. Full text in Research Archive Show summary

  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 (m5C) is implicated in cancer and recent data linked the gene expression of m5C writers, erasers and readers to diabetes, a well-known co-morbidity of obesity. Here, we tested whether gene expression of m5C 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 utilized 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. Results: We observed that multiple m5C 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 m5C regulator expression with macrophages was observed in OVAT compared to its SAT counterpart. Correlations between m5C regulators with important clinical variables related to obesity were observed in all three cohorts. Conclusion: Our findings provide evidence for adipose tissue depot-specific gene expression of m5C regulators that correlate with clinical variables of obesity.

• Svensson, Stina Ingrid Alice; Saeed, Sadia; Hoffmann, Anne; Ghosh, Adhideb; Wolfrum, Christian & Dahl, Mai Britt [Show all 15 contributors for this article] (2025). HOOK1 Gene Expression and DNA Methylation in Obesity and Related Cardiometabolic Traits. Obesity Facts. ISSN 1662-4025. doi: 10.1159/000547603. Full text in Research Archive Show summary

  Introduction: Accumulation of fat in omental visceral adipose tissue (OVAT) is strongly linked to metabolic diseases. Our recent findings show a distinct and more accessible chromatin landscape of the visceral depot compared to its subcutaneous counterpart. Based on integrated analysis of chromatin accessibility and transcriptomics, we identified previously unrecognised genes linked with obesity. Here, we performed in-depth analyses of one of the candidates, HOOK1, and tested for depot-specific gene expression, correlation with clinical traits and regulatory mechanisms including DNA methylation. Methods: We utilised intra-individually paired adipose tissue samples of human OVAT and subcutaneous adipose tissue (SAT) from our in-house cohort (N = 78). Gene expression was measured using real-time quantitative PCR and pyrosequencing was used to determine DNA methylation levels. Data were analysed for differential gene expression and DNA methylation differences between SAT and OVAT, along with correlation analyses with clinical variables related to obesity. Results were validated in adipose tissue samples from 1,618 donors of the Leipzig Obesity Biobank. Results: We observed consistently higher HOOK1 gene expression in OVAT compared to SAT and successfully confirmed this effect direction in several validation cohorts. We further identified that HOOK1 gene expression correlated with body mass index and hip circumference. We discovered a relationship between DNA methylation of the HOOK1 promoter with clinical variables important for liver function. Conclusion: Our data show that HOOK1 gene expression is adipose tissue depot-specific. We observed that gene expression and DNA methylation are correlated to clinical variables of obesity, suggesting that HOOK1 may play a role in obesity and its sequelae.

• Saeed, Sadia; Hoffmann, Anne; Svensson, Stina Ingrid Alice; Visnovska, Martina; Hagemann, Tobias & Ghosh, Adhideb [Show all 13 contributors for this article] (2025). Integrative analysis of gene expression and histone modifications for DES, DSP, GJA1 and SMOC2 in adipose tissue reveals potential relationship to cardiometabolic health. Molecular medicine (Cambridge, Mass. Print). ISSN 1076-1551. 31. doi: 10.1186/s10020-025-01391-3. Full text in Research Archive Show summary

  Abstract Background Adipose tissue influences cardiometabolic health through its endocrine activity and its role in regulating inflammation, lipid metabolism, and cardiovascular function. The expression of cardiac-associated genes within adipose tissue may reflect or contribute to cardiometabolic risk, yet this relationship remains poorly understood. This study investigates the expression profiles of the cardiac function associated genes GJA1 , DES , DSP and SMOC2 in human adipose tissue, and analyses their associations with cardiometabolic traits. Additionally, we explore epigenomic mechanisms that may underlie their differential gene expression. Methods Expression profiling and functional enrichment analyses were conducted to identify depot-specific cardiac gene expression patterns. Quantitative PCR validated gene expression in paired subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples from 78 individuals with obesity. Gene expression was further validated in three independent cohorts ( N  = 1,548 total). Associations with clinical traits were assessed using Spearman correlations and multivariate linear regression, adjusted for age, sex, and BMI. Integration with transcriptomic and proteomic datasets publicly available from the Adipose Tissue Knowledge Portal was performed to strengthen clinical relevance. Epigenomic profiling using genome-wide ChIP-seq for histone marks (H3K4me3, H3K4me1, H3K27ac, H3K27me3) was conducted in paired SAT and OVAT samples from five individuals. Results DES , DSP , GJA1 , and SMOC2 were significantly upregulated in OVAT compared to SAT. DES , DSP , and SMOC2 showed consistent expression patterns across all cohorts, while GJA1 exhibited context-dependent regulation. Gene expression in SAT was negatively correlated with cardiometabolic traits, including blood pressure, insulin resistance, and liver function markers. These associations were confirmed by regression analysis and supported by publicly available multi-omics data. Epigenetic analyses revealed OVAT-specific enrichment of active histone marks and reduced repressive marks, supporting higher differential transcriptional activity in OVAT. Conclusions Depot-specific gene expression of DES , DSP , and SMOC2 in adipose tissue is robustly linked to cardiometabolic traits and supported by distinct epigenetic landscapes in OVAT vs SAT, highlighting their potential as novel biomarkers for cardiometabolic health.

• Rønningen, Torunn; Zeng, Yong; Dahl, Mai Britt; Wang, Junbai; Visnovska, Martina & Tannæs, Tone Møller [Show all 18 contributors for this article] (2025). Global mapping of RNA N6-methyladenosine (m6A) in human subcutaneous and visceral adipose tissue reveals novel targets that correlate with clinical variables of obesity. Biomarker Research. 13(1). doi: 10.1186/s40364-025-00857-0. Full text in Research Archive Show summary

  Abstract Background Obesity is a major health challenge and fat accumulation in visceral depots is more strongly associated with metabolic comorbidities than deposition in subcutaneous depots. Epitranscriptomic regulation of gene expression by N 6 -methyladenosine (m 6 A) influences various aspects of RNA metabolism, however the m 6 A methylome in human adipose tissue and its relationship with fat distribution has not yet been investigated in detail. Methods In this study, we performed epitranscriptomic mapping of m 6 A in intra-individually paired samples of subcutaneous (SAT) and omental visceral adipose tissue (OVAT) from women with normal weight (BMI ≤25, n  = 3) and obesity (BMI ≥35, n  = 10) using meRIP-seq (discovery cohort). We further investigated differential m 6 A methylation for specific target genes in a larger cohort of individuals with obesity ( n  = 72, validation cohort) using meRIP-qPCR. meRIP-seq was performed for primary adipocytes from a subset of the patients ( n  = 4) to account for cell type specific differences. Results We here provide the first global map of m 6 A in human adipose tissue in paired samples of SAT and OVAT. We show an overall high overlap in m 6 A sites between individuals and depots, but also distinct depot-specific differences. We identify 339 target genes showing depot-specific m 6 A methylation. Depot-specific methylation was validated for selected sites in SEMA3A , SNAP47 and PPP1R9A in a larger validation cohort. We additionally identify differentially methylated targets between lean individuals and individuals with obesity, including TSC22D1 , FMNL2 and IL1R1 . By combining data from primary adipocytes with data from corresponding bulk adipose tissue, we identified a higher number of genes containing m 6 A in non-adipocyte cells in OVAT compared to SAT. Mechanistically, we show for selected targets that m 6 A affects RNA lifetime in pre-adipocyte cell culture models. Importantly, m 6 A methylation in selected targets correlates with clinically important variables related to obesity, fat distribution and glucose metabolism. Conclusions We identify a catalogue of novel targets showing adipose tissue depot specific m 6 A methylation, with potential as biomarkers in metabolic disease. Our findings underscore the regulatory role of m 6 A in obesity and provide valuable insights for future research. The datasets generated represent a significant resource for further insight in adipose tissue biology and its implications for metabolic health.

• Keller, Maria; Vogel, Mandy; Garten, Antje; Svensson, Stina Ingrid Alice; Rossi, Elena & Kovacs, Peter [Show all 8 contributors for this article] (2025). Epigenetics of Childhood Obesity. Hormone Research in Paediatrics. ISSN 1663-2818. doi: 10.1159/000543467. Full text in Research Archive Show summary

  Background: Childhood obesity has become a global pandemic and is one of the strongest risk factors for cardiovascular disease later in life. The correlation of epigenetic marks with obesity and related traits is being elucidated. This review summarizes the latest research and its challenges in the study of epigenetics of (childhood) obesity. Summary: Epigenome-wide association studies helped identify novel targets and methylation sites that are important in the pathophysiology of obesity. In the future, such sites will become essential for developing methylation risk scores (MRS) for metabolic and cardiovascular diseases. Although MRS are very promising for predicting the individual risk of obesity, the implementation of MRS is challenging and has not been introduced into clinical practice so far. Key Messages: Future research will undoubtedly discover numerous methylation sites that may be involved in the development of obesity and its comorbidities, especially at a young age. This will contribute to a better understanding of the complex etiology of human obesity. From a clinical perspective, the overarching aim was to generate MRS that is robust for reliable and accurate prediction of obesity and its comorbidities.

• Keller, Maria; Svensson, Stina Ingrid Alice; Rohde-Zimmermann, Kerstin; Kovacs, Peter & Böttcher, Yvonne (2023). Genetics and Epigenetics in Obesity: What Do We Know so Far? Current Obesity Reports. 12, p. 482–501. doi: 10.1007/s13679-023-00526-z. Full text in Research Archive Show summary

  Abstract Purpose of Review Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review highlights current research and its challenges in genetics and epigenetics of obesity. Recent Findings Recent progress in genetics of polygenic traits, particularly represented by genome-wide association studies, led to the discovery of hundreds of genetic variants associated with obesity, which allows constructing polygenic risk scores (PGS). In addition, epigenome-wide association studies helped identifying novel targets and methylation sites being important in the pathophysiology of obesity and which are essential for the generation of methylation risk scores (MRS). Despite their great potential for predicting the individual risk for obesity, the use of PGS and MRS remains challenging. Summary Future research will likely discover more loci being involved in obesity, which will contribute to better understanding of the complex etiology of human obesity. The ultimate goal from a clinical perspective will be generating highly robust and accurate prediction scores allowing clinicians to predict obesity as well as individual responses to body weight loss-specific life-style interventions.

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