Characterizing Alternative Splicing in Adipose Tissue Function and Metabolic Disease

Obesity is a complex disease, with both environmental and genetic causes, and it confers a significant global health burden while remaining difficult to treat and prevent. A better understanding of the risk factors that lead to disease and the underlying regulatory responses of specific disease states can provide insight into possible new treatments and interventions to improve health outcomes worldwide. Here, I provide insight into both environmental and genetic causes for obesity through two parallel studies. First, I investigate one of the main environmental factors leading to obesity: diet. In particular, I dissect the impact of differences in dietary macronutrient composition on metabolic measures and gene regulation in adipose tissue, measuring both gene expression and splicing changes. I identify thousands of genes and exons that are responsive to dietary macronutrient composition in adipose tissue, and link them to specific macronutrient patterns and cellular functions. One particularly strong gene regulatory response is the differential expression of genes associated with Bardet-Biedl syndrome in response to dietary fat content. In my second study, I expand our understanding of the contribution of genetics to obesity through assaying alternative splicing across the differentiation of preadipocytes isolated from lean, obese, and obese with type 2 diabetes (T2D) individuals. I find that splicing is highly dynamic across adipocyte differentiation and is impacted by metabolic phenotype. I also find that there is significant enrichment for an overlap between regions that are differentially spliced across adipocyte differentiation and variants that are associated with T2D. In both studies, I find that there is very little overlap between genes that are differentially expressed in response to the perturbation of interest and those that are differentially spliced. These results suggest that alternative splicing and expression may represent largely separate modes of gene regulation, and that studies that seek to describe gene regulatory responses to stimuli should strive to measure alternative splicing in addition to gene expression to capture a more complete picture of the gene regulatory change. Overall, these studies provide insight into adipose tissue function and both environmental and genetic risk for obesity, and can serve as a resource to guide future variant-to-function studies.