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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
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posted on 2022-03-15, 18:48 authored by Joji Kusuyama, Nathan S. Makarewicz, Brent G. Albertson, Ana Barbara Alves-Wagner, Royce H. Conlin, Noah B Prince, Christiano R. R. Alves, Krithika Ramachandran, Chisayo Kozuka, Yang Xiudong, Yang Xia, Michael F. Hirshman, Toshihisa Hatta, Ryoichi Nagatomi, Eva S. Nozik, Laurie J. GoodyearPreclinical
studies reveal maternal exercise as a promising intervention to reduce the
transmission of multi-generational metabolic dysfunction caused by maternal
obesity. The benefits of maternal exercise on offspring
health may arise from multiple factors and have recently been shown to involve
DNA demethylation of critical hepatic genes leading to enhanced glucose
metabolism in offspring. Histone modification is another epigenetic
regulator, yet the effects of maternal obesity and exercise on histone
methylation in offspring are not known. Here, we find that maternal high fat
diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose
metabolism in C57BL/6 mice through mechanism involving increased reactive
oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation
of H3K4 methyltransferase leading to decreased H3K4me3 at the promoters of
glucose metabolic genes. Remarkably, the entire signal was restored if the
HFD-fed dams had exercised during pregnancy. WDR82 overexpression in
hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels.
Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with
N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression
and glucose metabolism. Maternal exercise regulates a multi-component
epigenetic system in fetal liver resulting in the transmission of the benefits
of exercise to offspring.