Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation

• DOI: 10.2337/db21-0706
• Publication Date: 2022-03-15T18:38:27Z
• Authors: Joji Kusuyama; Nathan S. Makarewicz; Brent G. Albertson; Ana Barbara Alves...; Royce H. Conlin; Noah B. Prince; Christiano R.R. A...; Krithika Ramachan...; Chisayo Kozuka; Yang Xiudong; Yang Xia; Michael F. Hirshman; Toshihisa Hatta; Ryoichi Nagatomi; Eva S. Nozik; Laurie J. Goodyear
• Keywords: H3K4me3

Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by obesity. The benefits on offspring health may arise from multiple factors and have recently been shown involve DNA demethylation critical hepatic genes leading enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet effects obesity histone methylation are not known. Here, we find that high-fat diet (HFD; 60% kcal fat) induced dysregulation liver C57BL/6 mice through mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, inactivation H3 lysine 4 (H3K4) methyltransferase decreased H3K4me3 at promoters genes. Remarkably, entire signal was restored if HFD-fed dams had exercised during pregnancy. WDR82 overexpression hepatoblasts mimicked levels. Placental superoxide dismutase 3 (SOD3), but antioxidant treatment with N-acetylcysteine necessary for regulation H3K4me3, gene expression, metabolism. Maternal regulates multicomponent system fetal resulting