Poor maternal diet and obesity increase the risk of obesity and type 2 diabetes in offspring, fueling the worldwide epidemic of these diseases. Recent animal studies have shown that maternal exercise (MatEx) improves the metabolic phenotype of offspring in adulthood, including improved glucose tolerance and liver function. Here, we determined the molecular mechanisms responsible for these critical effects of MatEx. Female mice were fed a chow or high fat diet and housed in cages with (Trained) or without (Sedentary) running wheels for 2 wks prior to breeding and during gestation. Offspring were sedentary and chow-fed. MatEx improved glucose tolerance and liver function in adult offspring. Beginning at embryonic day 13.5, MatEx increased expression of TCA cycle and fatty acid oxidation genes in offspring liver, and increased DNA demethylation at promoters of these hepatic genes. Next, we identified a novel MatEx-induced AMPK/isocitrate dehydrogenase/αketoglutarate/Tet axis in offspring liver controlling DNA demethylation. Primary hepatoblasts treated with serum from trained dams, but not sedentary dams or trained non-pregnant females stimulated this pathway, suggesting the effects of MatEx on offspring stem from a placenta-derived serum factor(s). LC-MS/MS of serum and RNAseq of placenta from trained dams identified this factor as superoxide dismutase 3 (Sod3), and recombinant SOD3 treatment of hepatoblasts increased AMPK-Tet signaling and hepatic gene expression. The effects of MatEx to increase liver AMPK-Tet signal, alter liver DNA methylation and gene expression, and improve offspring glucose tolerance in vivo were ablated in placenta-specific Sod3 KO mice. Finally, SOD3 was increased in serum and placenta from highly physically active pregnant women. Sod3 is an exercise-induced, placenta-derived protein that improves glucose homeostasis via epigenetic changes in offspring liver, defining a novel paradigm for the beneficial effects of exercise on metabolic health.
J. Kusuyama: None. A.B. Wagner: None. R.H. Conlin: None. N.S. Makarewicz: None. M. Møller: None. E.M. Miele: None. R. Middelbeek: None. N. Jessen: None. P.G. Ovesen: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen, Colgate-Palmolive, Eli Lilly and Company, Medtronic. K.B. Adamo: None. E.N. Grayck: None. L.J. Goodyear: None.
National Institutes of Health (DK101043)