Alternative mRNA Splicing in the Pathogenesis of Obesity

Mabel Yau,Lu Xu,Chi-Ming Wong

doi:10.3390/ijms19020632

Abstract

Alternative mRNA splicing is an important mechanism in expansion of proteome diversity by production of multiple protein isoforms. However, emerging evidence indicates that only a limited number of annotated protein isoforms by alternative splicing are detected, and the coding sequence of alternative splice variants usually is only slightly different from that of the canonical sequence. Nevertheless, mis-splicing is associated with a large array of human diseases. Previous reviews mainly focused on hereditary and somatic mutations in cis-acting RNA sequence elements and trans-acting splicing factors. The importance of environmental perturbations contributed to mis-splicing is not assessed. As significant changes in exon skipping and splicing factors expression levels are observed with diet-induced obesity, this review focuses on several well-known alternatively spliced metabolic factors and discusses recent advances in the regulation of the expressions of splice variants under the pathophysiological conditions of obesity. The potential of targeting the alternative mRNA mis-splicing for obesity-associated diseases therapies will also be discussed.

Highlights

Alternative mRNA splicing plays a key role in enhancing protein diversity [1]
Further functional verification is required to confirm the bioinformatics study, the findings strongly suggested that, the main function of generating multiple protein isoforms by alternative mRNA splicing is for generating protein isoforms
Nusinersen promotes the inclusion of exon 7 by binding to intron splicing silencer-N1 and increasing the production of full length SMN2 protein [120]

Summary

Introduction

Alternative mRNA splicing plays a key role in enhancing protein diversity [1]. Based on a recent analysis of the statistics for annotated human nuclear genes in GeneBase 1.1, nearly 80% of human protein-coding genes produce more than one transcript [2]. Human protein-coding genes contain ~11 exons per transcript and produce 5.4 mRNAs per gene. It is generally accepted that alternative mRNA splicing of exons is mainly for the production of multiple protein isoforms from the same gene [1]. Recent transcriptome analysis demonstrated highly alternative mRNA transcripts have similar coding sequences to that of the canonical isoforms, and the sites for protein-protein interaction are usually protected from alternative splicing-mediated removals [12]. Significant changes in the expression level of splice variants and splicing factors in association with age and metabolic dysregulation in animal models, as well as in human populations, had already been reported [25,26,27,28,29,30]. The possibility by modulation of the expression level and activity of those splicing factors as potential therapeutic targets for obesity-associated metabolic complications will be discussed

Mis-Splicing of Metabolic Factors in Obesity

Leptin Receptor

Nuclear Receptor Corepressor

Findings

Conclusions