Metabolic adaptation is often framed as differential gene expression, yet nutrient state also remodels which transcript isoforms from a gene contribute to physiology. This review presents isoform usage as an organizing principle of endocrine and metabolic regulation: a layer that connects nutrient sensing to transcript architecture, protein function, tissue specialization, and disease vulnerability. We synthesize evidence that fasting, feeding, insulin, and metabolite availability reshape isoform outputs across metabolic organs independently of total mRNA abundance. We then integrate functional examples, nutrient-responsive RNA-processing mechanisms, human genetic and disease data, and emerging RNA-targeted interventions. These findings suggest that metabolic disease reflects not only dysregulated gene expression but also failure to maintain the appropriate isoform state required for adaptive physiology.

Kedan and Zauber et al. combine long-read transcriptomics with molecular-weight-resolved proteomics to generate an integrated landscape of mRNA and protein isoforms. Their IsoFrac framework enables scalable protein isoform discovery, revealing that numerous shorter protein variants contribute substantially to human proteome complexity.

Proceedings of the National Academy of Sciences, Volume 123, Issue 38, September 2026. SignificanceTranscripts of genes are translated into protein isoforms, which play crucial roles in biological processes; dysregulation of translation can generate disease. In large-scale studies, however, accurately estimating isoform abundances is ...

Key plasma protein, including albumin, complement system proteins, and coagulation factors circulate in biochemically and functionally distinct isoforms, or proteoforms. Despite the importance of thes...

RT&T-AMP-MERFISH enables whole-transcriptome-scale, isoform-resolved spatial imaging of single cells in intact tissues and reveals how gene programs and transcript isoform usage vary across cell types...