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Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.
Joji Kusuyama,Laurie J Goodyear
Joji Kusuyama,Ana Barbara Alves-Wagner,Royce H Conlin,Nathan S Makarewicz,Brent G Albertson,Noah B Prince,Shio Kobayashi,Chisayo Kozuka,Magnus Møller,Mette Bjerre,Jens Fuglsang,Emily Miele,Roeland JW Middelbeek,Yang Xiudong,Yang Xia,Léa Garneau,Jayonta Bhattacharjee,Céline Aguer,Mary Elizabeth Patti,Michael F Hirshman,Niels Jessen,Toshihisa Hatta,Per Glud Ovesen,Kristi B Adamo,Eva Nozik-Grayck,Laurie J Goodyear