Transcriptional and epigenetic alterations associated with obesity and Type 2 diabetes

Obesity and type 2 diabetes (T2D) are major global health issues. While genetic predisposition and lifestyle choices are known to be the main risk factors, the etiology of the conditions is still incompletely understood. Here, we combined the findings of three independent studies to elucidate molecular mechanisms that underlie metabolic changes in the skeletal muscle in response to bariatric surgery and aerobic exercise. We applied an integrative bioinformatic approach to transcriptome and DNA methylome data of skeletal muscle from people with overweight, obesity, and T2D who underwent bariatric surgery or aerobic exercise training. The methods used included pathway enrichment analyses, least absolute shrinkage and selection operator regression (LASSO), and weighted gene correlation analysis (WGCNA). We found that bariatric surgery restores most of the skeletal muscle transcriptome and methylome to levels of lean people within the first year in obese individuals without T2D. Moreover, we identified marker genes which are simultaneously predictive of weight loss as well as a decrease in circulating free fatty acid levels. Furthermore, individuals with obesity and T2D exhibited baseline differences and differential transcriptional response to bariatric surgery compared to individuals without T2D, likely due to differences in epigenetic plasticity. Finally, expression data of people who did not improve insulin sensitivity through aerobic exercise training indicated an aberrant skeletal muscle mitochondrial metabolism and improper extracellular matrix remodeling. A comprehensive analysis of affected genes in all three studies highlighted mitochondrial function, fatty acid metabolism, and inflammation as key processes through which skeletal muscle contributes to whole-body metabolism in response to both bariatric surgery and exercise. Extracellular matrix remodeling seemed to be more extensively affected after exercise, which could suggest that exercise is necessary for better restoration of muscle function. The different studies presented in this thesis demonstrate multidimensional links between the improvement of metabolism, skeletal muscle transcriptome, and methylome in response to two weight loss interventions, namely bariatric surgery and exercise.