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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 15.03.2022, 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. Goodyear
Preclinical 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.

Funding

This work was supported by NIH grant R01DK101043 (to L.J.G.), P30DK036836 (DRC to Joslin Diabetes Center), 1R35HL139726 (to E.S.N.), P30DK036836 (DRC to Joslin Diabetes Center), by American Diabetes Association (training grant number 1-17-PMF-009 [to A.B. A-W]); and by JSPS KAKENHI Grant Number 21H03315 (to J.K.).

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