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Butyrate Counteracts Maternal Obesity-Induced Cardiac Defects by Promoting PLEKHG3-Actin Binding

ABSTRACT: Maternal obesity increases the risk of abnormal cardiac development during gestation. However, the underlying metabolic determinants contributing to these defects remain insufficiently understood. In this study, a significant reduction was identified in butyrate levels in high-fat diet (HFD)-fed mice and their embryos, which exhibited disrupted cardiac morphology and function. These abnormalities included ventricular wall thickening, cardiomyocyte (CM) hypertrophy, sarcomere elongation, and myofibril disorganization, all of which were reversed by butyrate supplementation. Consistent results were observed in in vitro models using palmitic acid treated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and organoids. Mechanistically, drug affinity-responsive target stability (DARTS) assays and molecular docking analyses identified PLEKHG3 as a direct target of butyrate. Butyrate binding enhanced the interaction between PLEKHG3 and F-Actin, thereby promoting CM contractility and the orderly assembly of myofibrils. Conversely, loss-of-function mutation of Q175A in PLEKHG3 disrupted PLEKHG3 / F-Actin binding and abrogated the protective effects of butyrate under high-fat conditions. Collectively, these findings reveal that butyrate ameliorates obesity-induced embryonic cardiac defects by modulating the PLEKHG3 / F-Actin axis, highlighting its potential as a therapeutic metabolite for mitigating cardiac abnormalities associated with maternal obesity.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE327308 | GEO | 2026/08/25

REPOSITORIES: GEO

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Butyrate Counteracts Maternal Obesity-Induced Cardiac Defects by Promoting PLEKHG3-Actin Binding

Project description:Butyrate Counteracts Maternal Obesity-Induced Cardiac Defects by Promoting PLEKHG3-Actin Binding

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