Bariatric surgery induces distinct transcriptional and epigenetic changes in skeletal muscle of obese people with and without type 2 diabetes

Introduction Bariatric surgery remains the most effective obesity intervention. To investigate molecular mechanisms underlying the clinical outcomes, we compared skeletal muscle transcriptome and DNA methylome before and one year after bariatric surgery of obese individuals without (OB, n=13) and with type 2 diabetes (T2D, n=13), and identified genes that contribute to improved metabolic characteristics in each group.

Methods We applied several in silico analyses to gene expression (RNA-sequencing) and DNA methylation data (MethylationEPIC 850K), including a machine learning approach (LASSO) to identify genes whose expression levels were predictive of clinical traits.

Results Participants with and without T2D exhibited a high number of differentially expressed genes (DEG) (q<0.05) before (2718 DEG) and after (2881 DEG) surgery. Pathway enrichment analysis indicated that both groups altered expression of DNA repair, insulin and PPAR signaling pathway genes. We identified major contributors of several clinical traits, including whole-body insulin sensitivity. For example, INTS11 and HMGA1 were identified as top predictors of HbA1c, free fatty acid clearance and insulin sensitivity in OB and T2D, respectively. Furthermore, in T2D participants only 49% of DEG were also differentially methylated, compared to 71% in OB.

Conclusion We provide a comprehensive overview of differential skeletal muscle transcriptome responses to bariatric surgery of obese individuals with and without T2D and identify predictors of improved metabolic traits. Additionally, T2D skeletal muscle appears to be less susceptible to changes in DNA methylation, potentially due to genetic differences and/or medication.

Publikationsverlauf

Artikel online veröffentlicht:
02. Mai 2023