Aims: Regular exercise promotes the beiging and metabolic adaptations of white adipose tissue (WAT) through the cumulative transcriptional responses that occur after each exercise session. However, the effects of a single bout of acute exercise and the role of N6-methyladenosine (m6A) in these adaptations remain unclear. We aim to investigate this further.
Materials and methods: We constructed mouse models for chronic (8 weeks of running) and acute (single 1-hour run) exercise to study the effects on white adipose tissue (WAT) metabolism and beiging through metabolic phenotyping and transcriptome sequencing. Additionally, we explored the impact of acute exercise on WAT m6A modification and target genes, combining m6A regulators with cell models to elucidate the role of m6A in WAT exercise adaptation.
Key findings: Here, we reveal that upregulated m6A modification after acute exercise induces the formation of glycolytic beige fat (g-beige fat) in WAT. Mechanistically, the metabolite β-hydroxybutyrate (BHBA) secreted after acute exercise upregulates m6A modification in WAT. This enhances m6A-dependent translation of the histone acetyltransferase CREBBP, promoting the transcription of key beiging genes by increasing chromatin accessibility. Pharmacologically elevating circulating BHBA mimics the metabolic response induced by acute exercise, upregulating m6A modification and its downstream signals. Additionally, BHBA exhibits long-term effects, improving metabolic homeostasis in obesity by promoting thermogenesis in WAT.
Significance: Our results reveal the role of metabolites in WAT metabolic adaptation through m6A-mediated chromatin accessibility after acute exercise, providing a novel therapeutic target for regulating WAT metabolism from a nutritional epigenetics perspective.
Keywords: Adipose tissue; Beiging; Exercise; m(6)A; β-hydroxybutyrate.
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