Abstract
Alternative splicing (AS) is a fundamental mechanism for enhancing transcriptome diversity and regulating gene expression, crucial for various cellular processes and the development of complex traits. This review examines the role of AS in metabolic disorders, including obesity, weight loss, dyslipidemias, and metabolic syndrome. We explore the molecular mechanisms underlying AS regulation, focusing on the interplay between cis-acting elements and trans-acting factors, and the influence of RNA-binding proteins (RBPs). Advances in high-throughput sequencing and bioinformatics have unveiled the extensive landscape of AS events across different tissues and conditions, highlighting the importance of tissue-specific splicing in metabolic regulation. We discuss the impact of genetic variants on AS, with a particular emphasis on splicing quantitative trait loci (sQTLs) and their association with cardiometabolic traits. The review also covers the regulation of spliceosome components by phosphorylation, the role of m6A modification in AS, and the interaction between transcription and splicing. Additionally, we address the clinical relevance of AS, illustrating how splicing misregulation contributes to metabolic diseases and the potential for therapeutic interventions targeting splicing mechanisms. This comprehensive overview underscores the significance of AS in metabolic health and disease, advocating for further research to harness its therapeutic potential.