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Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational 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 a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (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 multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

Recent studies demonstrate that adaptations to white adipose tissue are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal white adipose tissue (iWAT) in male mice including decreasing fat mass, improving mitochondrial function, inducing beiging and stimulating the secretion of adipokines. Here, we find that despite performing more voluntary wheel running compared to males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor co-activators are upregulated in iWAT from trained male mice, and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex-specificity also occurs in the secretome profile, as we identify Cysteine Rich Secretory Protein 1(Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females, and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

Maternal and paternal obesity and type 2 diabetes are recognized risk factors for the development of metabolic dysfunction in offspring, even when the offspring follow a healthful lifestyle. Multiple studies have demonstrated that regular physical activity in mothers and fathers has striking beneficial effects on offspring health, including preventing the development of metabolic disease in rodent offspring as they age. Here, we review the benefits of maternal and paternal exercise in combating the development of metabolic dysfunction in adult offspring, focusing on offspring glucose homeostasis and adaptations to metabolic tissues. We discuss recent findings regarding the roles of the placenta and sperm in mediating the effects of parental exercise on offspring metabolic health, as well as the mechanisms hypothesized to underlie these beneficial changes. Given the worldwide epidemics of obesity and type 2 diabetes, if these findings translate to humans, regular exercise during the reproductive years might limit the vicious cycles in which increased metabolic risk propagates across generations.

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.

Maternal obesity and diet are critical risk factors for development of obesity and diabetes in both first (F1) and second (F2) generation offspring. Maternal exercise in mice improves F1 metabolic health and prevents the detrimental effects of maternal high-fat-diet (HFD) on F1 offspring. Whether the beneficial effects of maternal exercise can be transmitted to the F2 generation is unknown. Here, C57BL/6 females were fed a chow or HFD and subdivided into cages with (Exercise) or without (Sedentary) running wheels for 2wks before breeding and during ∼3wks gestation. Male F1 offspring were sedentary and chow-fed, and at 8 wks of age were bred with age-matched females from untreated parents. F2 offspring were studied based on grand-maternal treatment: chow sedentary; chow trained; HFD sedentary; HFD trained (n= ∼10 litters/group; 348 total mice). F2 offspring were sedentary and chow-fed and studied up to 52 wks of age. For F2 males, grand-maternal exercise significantly improved glucose tolerance at 24, 36 and 52 wks and decreased insulin concentrations at 52 wks. Grand-maternal exercise also resulted in F2 males with lower body weights, decreased fat mass and increased lean mass at 52wks. Grand-maternal HFD decreased glucose uptake in skeletal muscles and adipose tissue in F2 males, but there was no effect of grand-maternal exercise, suggesting that the mechanism for improved glucose tolerance in F2 males does not involve glucose uptake in these tissues. For female F2, grand-maternal exercise had no effect on insulin concentrations, body weights or tissue glucose uptake. However, grand-maternal exercise significantly improved glucose tolerance in female F2 at 36 and 52 wks, and decreased fat mass and increased lean mass. Maternal exercise has beneficial effects on the metabolic health of adult F2 male and female offspring. These novel findings suggest that maternal exercise can prevent obesity and diabetes in multiple generations and may help reduce the incidence of these diseases worldwide. Disclosure A.B.A. Wagner: None. J. Kusuyama: None. P. Nigro: None. N.S. Makarewicz: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen, Colgate-Palmolive, Eli Lilly and Company, Medtronic. L.J. Goodyear: None. Funding American Diabetes Association (1-17-PMF-009 to A.B.A.W.); National Institutes of Health (R01DK101043)

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. Disclosure 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. Funding National Institutes of Health (DK101043)