# FTO-dependent m6A methylation mediates gestational diabetes mellitus-induced offspring cardiac senescent hypertrophy and dysfunction

## TL;DR

This study shows how gestational diabetes affects offspring heart health through FTO protein and RNA methylation, suggesting new treatment approaches.

## Contribution

The study reveals FTO-dependent m6A methylation as a novel mechanism linking gestational diabetes to offspring cardiac dysfunction.

## Key findings

- GDM represses FTO, increasing m6A methylation and causing cardiac hypertrophy in offspring.
- FTO restoration reverses GDM-induced cardiac senescence and mitochondrial defects.
- Targeting the FTO/m6A axis may prevent GDM-related cardiac programming in offspring.

## Abstract

Fat mass and obesity-associated (FTO) protein plays a critical role in N6-methyladenosine (m6A) demethylation, linked to metabolic disorders such as diabetes and obesity. This study investigates FTO-dependent m6A methylation in fetal programming of cardiac dysfunction due to gestational diabetes mellitus (GDM). Using a Sprague-Dawley rat model of GDM, we observed that GDM exposure repressed FTO, increasing m6A RNA methylation, consequently developing a cardiac hypertrophic dysfunctional phenotype in neonatal offspring. FTO inhibition replicated the effects of GDM, while overexpression of FTO via FTO lentivirus (Lenti-FTO) reversed GDM-induced hypertrophy, cardiac senescence, and dysfunction. These results illuminate the molecular mechanisms by which GDM negatively impacts offspring cardiac health and highlight the potential for targeting FTO-mediated RNA methylation pathways as a therapeutic strategy for GDM-related cardiac issues.

•GDM represses cardiac FTO, increasing m6A methylation and hypertrophy in offspring•FTO-dependent m6A regulation links GDM to cardiac dysfunction in neonatal hearts•FTO restoration alleviates GDM-induced cardiac senescence and mitochondrial defects•Targeting the FTO/m6A axis may help prevent GDM-induced cardiac programming

GDM represses cardiac FTO, increasing m6A methylation and hypertrophy in offspring

FTO-dependent m6A regulation links GDM to cardiac dysfunction in neonatal hearts

FTO restoration alleviates GDM-induced cardiac senescence and mitochondrial defects

Targeting the FTO/m6A axis may help prevent GDM-induced cardiac programming

Molecular mechanism of gene regulation; Epigenetics