Epigenetic reprogramming of adipose tissue: Multi-omics insights into the effects of intermittent fasting

Objective: Intermittent fasting is an efficient strategy to improve insulin sensitivity and protect from metabolic diseases. This study investigates the molecular networks and epigenetic mechanisms underlying the beneficial effects of two intermittent fasting protocols, time-restricted feeding (TRF) and alternate-day fasting (ADF), in the diabetes-prone New Zealand Obese (NZO) mouse model.

Results: In-depth multi-omics analysis demonstrated significant alterations in the transcriptome, methylome, and miRNome of white adipose tissue (WAT), particularly in response to the more stringent ADF intervention. About 6,000 genes exhibited differential expression compared to an ad libitum-fed (AL) control group, with around 60% and 35% potentially regulated by altered DNA methylation and differentially expressed miRNAs, respectively. Although gene expression profiles induced by TRF and ADF exhibited minimal overlap, pathway enrichment analysis showed that similar metabolic processes were modulated, pointing to a common regulatory framework. Machine learning-based analysis uncovered a WAT module of around 3,000 co-expressed genes highly correlated with body weight. Genes within this module exhibited similar expression profiles in TRF and ADF, capturing the gradual response of WAT to intermittent fasting interventions of varying severity. Further integration with ChIP-X Enrichment Analysis 3 (ChEA3) identified the epigenetically regulated transcription factors Spi1 and Irf5 as key regulatory hub genes, potentially regulating about 30% of the module genes. The DNA methylation of SPI1 and IRF5 increase in human WAT and blood samples in response to bariatric surgery- induced weight loss. An altered DNA methylation of SPI1 and IRF5 associated with a higher risk incidence of type 2 diabetes in the EPIC Potsdam cohort. Importantly, SPI1 gene expression strongly correlated with body fat of a cross-sectional cohort, also reinforcing its relevance in human metabolic health. In a cohort of 200,000 participants, 21 rare null variants in IRF5 were associated to obesity-related traits, connecting genetic variation to metabolic outcomes.

Conclusion: This work emphasizes the role of intermittent fasting in modulating adipose tissue gene expression through epigenetic mechanisms, particularly DNA methylation. The key regulatory genes Spi1 and Irf5 are promising therapeutic targets for metabolic disorders.

Publication History

Article published online:
28 May 2025