Obesity and type 2 diabetes in mothers can initiate a vicious cycle of multi-generational metabolic dysfunction. Conversely, maternal exercise (MatEx) in mice improves offspring metabolic health. We previously found that the mechanism for this critical benefit of MatEx involves multiple epigenetic changes inducing increased expression of TCA and fatty acid oxidation (FAO) genes in offspring liver, leading to enhanced liver function. Here, we hypothesize that maternal high fat diet (MatHFD) and MatEx result in histone modifications, an important means of epigenetic regulation. C57BL/6 female mice were fed chow or HFD, housed with (trained) or without (sedentary) running wheels for 2 weeks before breeding and through gestation. Offspring were chow fed and sedentary and livers studied up to age 52 weeks. Trimethylation of lysine 4 on histone H3 (H3K4me3), a hallmark of active transcription, was decreased in promoters of TCA and FAO genes in offspring livers from MatHFD. Importantly, this decrease was fully reversed in offspring livers from MatEx. In fact, offspring livers from MatEx had increased H3K4me3 in these genes as early as embryonic day 13.5 and at all times after birth. Altered H3K4me3 was associated with changes in H3K4 methyltransferase (HKMT) activity, as MatHFD decreased, and MatEx increased HKMT activity in offspring livers. MatHFD induced protein carbonylation in offspring liver, and MatEx prevented this harmful effect on protein function. LC-MS/MS showed that WDR82, a regulatory component of HKMT, was robustly carbonylated in offspring liver of MatHFD, an effect reversed by MatEx. Overexpression of WDR82 in offspring hepatoblasts from MatHFD recovered H3K4me3 levels and hepatic gene expression. In sum, these data demonstrate that maternal exercise reverses the detrimental effects of maternal HFD on H3K4me3 function, likely via protection of WDR82 from carbonylation. We have identified a novel epigenetic mechanism by which maternal exercise improves offspring metabolic health.
J. Kusuyama: None. A.B. Wagner: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen Inc., Colgate-Palmolive Company, Medtronic. L.J. Goodyear: None.
National Institutes of Health (to L.J.G.); Sunstar Foundation (to J.K.)