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

A better understanding of gene regulation in metabolically unhealthy adipose tissue can provide insights into the mechanisms underlying adipose tissue dysfunction. We used RNA-seq data from a differentiation time course of lean individuals, individuals with obesity, and individuals with obesity and T2D to characterize alternative splicing in adipocyte function. Splicing was highly dynamic across adipocyte differentiation, and the dynamics of splicing were impacted by metabolic phenotype. There was little overlap between genes that were differentially spliced and those that were differentially expressed, positioning alternative splicing as an independent regulatory mechanism whose impact would be missed when looking at gene expression changes alone. We integrated our splicing results with GWAS for BMI and T2D, and found that T2D-associated variants were enriched in regions that were differentially spliced in early differentiation. These findings provide insight into the role of splicing in adipocyte differentiation and serve as a resource to guide variant-to-function studies.