Differential alternative polyadenylation response to high-fat diet between polygenic obese and healthy lean mice

Obesity's complex etiology due to the interplay of environment and genetics makes it a more challenging research and health problem. Some of the contributing genetic factors that have not yet been examined in detail entail mRNA polyadenylation (PA). Genes with multiple PA sites express mRNA isoforms differing in coding sequence or 30UTR through alternative polyadenylation (APA). Alterations in PA have been associated with various diseases; however, its contribution to obesity is not well-researched. Following an 11-week high-fat diet, the APA sites in the hypothalamus of two unique mouse models for polygenic obesity (Fat line) and healthy leanness (Lean line) were determined using whole tran-scriptome termini site sequencing (WTTS-seq). We found 17 genes of interest with differentially expressed APA (DE-APA) isoforms, among which seven were previously associated with obesity or obesity-related traits (Pdxdc1, Smyd3, Rpl14, Copg1, Pcna, Ric3, Stx3) but have not yet been studied in the context of APA. The remaining ten genes (Ccdc25, Dtd2, Gm14403, Hlf, Lyrm7, Mrpl3, Pisd-ps3, Sbsn, Slx1b, Spon1) represent novel candidates associated with obesity/adiposity due to variability brought about by differential usage of APA sites. Our results provide insights into the relationship between PA and the hypothalamus in the context of obesity, by being the first study of DE-APA sites and DE-APA isoforms in these mouse models. Future studies are needed further to explore the role of APA isoforms in polygenic obesity by expanding the scope of research to other metabolically important tissues (such as liver and adipose tissues) and investigating the potential for targeting PA as a therapeutic strategy for obesity management. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The complex etiology of obesity is influenced by both genetics and environment, making it a challenging research and health problem. This study focused on mRNA polyadenylation (PA) genes, which play a role in obesity but have not been extensively researched. Using mouse models, the researchers identified several genes with differentially expressed APA isoforms associated with obesity. These findings provide insights into potential therapeutic strategies for managing obesity.