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The lab of Dan Xu, PhD, assistant professor at The Hormel Institute, has published a groundbreaking study in Cell Metabolism, a highly prestigious scientific journal.

The paper, entitled “Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation,” reveals how the presence or lack of nutrients can shape how variations in some gene products (gene isoforms) are used —  independently of gene expression. This newly discovered regulatory layer plays a crucial role in metabolic adaptation, offering new insights into obesity and metabolic-related disorders.

This research project, co-led by Xu and Dr. Lei Sun, PhD (Duke-NUS Medical School, Singapore), could pave the way for RNA-based therapies targeting metabolic diseases like obesity and type 2 diabetes.

Cells are metabolic masters, constantly adjusting to changes in nutrients by tweaking enzymes, signaling pathways (sequences of chemical reactions that carry out a cell function), and even gene expression (turning a gene’s instructions into a function or product, such as  a protein).

Thanks to “alternative isoform usage,” cells can mix and match gene segments (splicing) to create different proteins. This process affects ~95% of human genes, expanding genome diversity tenfold. Proper isoform regulation is key for cell development, while dysregulation is linked to diseases like cancer and muscular dystrophy. With metabolic diseases on the rise, understanding isoform usage in metabolism is more critical than ever.

The paper explores how alternative isoform usage helps the body adapt to nutrient changes across major metabolic organs and what role this usage plays in regulating metabolism. The researchers found isoform usage can change in response to nutrients in the environment — independently of overall gene expression. This previously overlooked layer of metabolic regulation demonstrates the body can fine-tune its metabolism beyond traditional gene expression changes.

“Alternative isoform usage occurs in about 95% of human genes,” Xu said. “If we can identify how it goes awry in metabolic disorders, we can develop RNA-based treatments to restore healthy regulation.”

Shengren Song, PhD, post-doctoral associate, and Franklin Nelson, researcher 1 at The Hormel Institute, are also listed as authors of the paper.