Paternal high fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation, nutrient transporter mRNA expression, and fetal weight in a sex-dependent manner

Authors: Larson, Kate; Bundy, Amy; Roemmich, James

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/4/2020
Publication Date: 3/15/2020
Citation: Larson, K.J., Bundy, A.N., Roemmich, J.N. 2020. Paternal high fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation, nutrient transporter mRNA expression, and fetal weight in a sex-dependent manner. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2020.108373.
DOI: https://doi.org/10.1016/j.jnutbio.2020.108373

Interpretive Summary: Several studies indicated that paternal obesity increases, while paternal exercise decreases, offspring obesity and type 2 diabetes risk; however, none had yet to determine whether a paternal high fat (HF) diet and exercise modify placental tissue weight and inflammation, fetal weight, and nutrient transport by changing sperm microRNA. Results in our current study also show that paternal HF diet decreases sperm’s epigenetic marker called dimethyl histone 3 lysin 9 (H3K9me2) protein expression. Paternal exercise also modified sperm expression of microRNA (miRNA) 193b and 204, a known regulator of gene expression. We also found that paternal HF diet decreases placental and fetal weights in placenta that are associated with male fetus while nutrient transporters (SLC6a19 and SLC38a2) and inflammatory factor (IL-1 beta and TNF-alpha) mRNA expression were altered only in placenta that are associated with female fetus. These results demonstrate that paternal HF diet and exercise influence placental and fetal weight, placental inflammation and nutrient transport in offspring in a sex-specific manner.

Technical Abstract: We have shown that male offspring (F1) of fathers (F0) fed a high fat (HF) diet and exercised had greater skeletal muscle insulin signaling and reduced T2DM risk. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by developmentally early alterations in epigenetics of placental tissue growth via changes in sperm miRNA expression. To test these hypotheses, three-week old male C57BL/6 mice were fed a normal-fat (NF) diet (16% fat) or a HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months prior to mating with NF diet fed dams. F0 sperm and placental tissue samples were collected to determine changes in placental and fetal weights, placental gene expression, and F0 sperm miRNA expression. F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of di-methylated histone 3 lysin 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males while no changes in the F1 females. Placental proinflammatory cytokine mRNA expression, including IL-1 beta and TNF-alpha, was reduced by paternal exercise while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise while placental inflammatory gene expression are influenced by paternal exercise in offspring in a sex-specific manner.