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

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.