Splicing across adipocyte differentiation is highly dynamic and impacted by metabolic phenotype

Adipose tissue dysfunction underlies many of the metabolic complications associated with obesity. A better understanding of the gene regulation differences present in metabolically unhealthy adipose tissue can provide insights into the mechanisms underlying adipose tissue dysfunction. Here, we used RNA-seq data collected from a differentiation time course of lean, obese, and obese with type 2 diabetes (T2D) individuals to characterize the role of alterative splicing in adipocyte differentiation and function. We found that splicing was highly dynamic across adipocyte differentiation in all three cohorts, and that the dynamics of splicing were significantly impacted by metabolic phenotype. We also found that there was very little overlap between genes that were differentially spliced in adipocyte differentiation and those that were differentially expressed, positioning alternative splicing as a largely independent gene regulatory mechanism whose impact would be missed when looking at gene expression changes alone. To assess the impact of alternative splicing across adipocyte differentiation on genetic risk for metabolic diseases, we integrated the differential splicing results generated here with genome-wide association study results for body mass index and T2D, and found that variants associated with T2D were enriched in regions that were differentially spliced in early differentiation. These findings provide insight into the role of alternative splicing in adipocyte differentiation and can serve as a resource to guide future variant-to-function studies.