Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation.

Area of Science:

• Molecular Biology
• Metabolomics
• Genomics

Background:

• Transcriptome modulation is key for metabolic adaptation.
• The role of alternative splicing and isoform usage in metabolic regulation is not fully understood.

Purpose of the Study:

• To investigate isoform usage modulation in major metabolic organs across diverse metabolic states in mice and monkeys.
• To identify conserved, nutrient-regulated isoform events across species and their correlation with human metabolic traits.
• To elucidate the regulatory mechanisms, particularly splicing factors, governing isoform usage in adipocytes.

Main Methods:

• Comparative transcriptomic analysis of major metabolic organs in mice and monkeys under varying nutrient conditions.
• Identification and analysis of nutrient-regulated alternative splicing events.
• Bioinformatic analysis of splicing factor-binding motifs.
• Validation using adipose tissue-specific knockout and transgenic mouse models.

Main Results:

• Numerous isoform usage events are modulated by nutrient challenges, largely independent of gene expression changes.
• Hundreds of conserved isoform events show consistent responses to nutrient challenges across mice and monkeys, correlating with human metabolic traits.
• HuR (Human antigen R) is identified as a key regulator of the adipocyte isoform network.

Conclusions:

• Isoform usage plays a significant, underappreciated role in metabolic adaptation and regulation.
• Conserved isoform events represent potential targets for understanding and modulating metabolic health across species.
• HuR is a critical orchestrator of isoform regulation in adipose tissue, impacting metabolic adaptation.