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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Research Project #436644

Research Project: Epigenetic Regulation of Obesity

Location: Healthy Body Weight Research

2022 Annual Report

Objective 1: Demonstrate effects of parental diet and exercise on placental epigenetic programming that affects offspring obesity and type 2 diabetes mellitus. Objective 2: Determine the effects of maternal dietary patterns on placental tissue epigenetic programming and central dopaminergic control of offspring eating behavior. Objective 3: Define intervention strategies to reverse placental programming induced by parental high-fat diet.

The maternal and paternal consumption of excess food energy leading to parental obesity contributes to the subsequent development of offspring obesity. This phenomenon, in part, involves the epigenetic transmission of obesity risk across generations. The overarching hypothesis of this proposal is that a parental high fat diet and sedentary conditions regulate offspring obesity risk via modifying early epigenetic programming of placental tissue. We propose to study how these placental changes result in adipose and skeletal tissues energy metabolism and eating behavior alterations in the offspring. The primary focus of this project will be on placental tissue epigenetic gene expression influencing placental structural alterations and inflammation resulting in maternal nutrient transport dysfunction. Both animal and human studies show that maternal and paternal diets and obesity adversely affect fetal growth by altering placental structure and function, resulting in adverse birth outcomes and offspring obesity. Our preliminary data demonstrate that placental inflammation and nutrient transporter gene expressions are influenced by parental diet and exercise. Our new research project is an extension of our current and previous projects in which we demonstrated that maternal low protein and high fat diets increase placental tissue scarring, resulting in neovascularization and inflammation that increase offspring obesity and type 2 diabetes mellitus (T2DM) risks. There is little research on how maternal and paternal diets and exercise influence offspring obesity and T2DM risks via epigenetic-induced alterations in placental tissue function. Research results from this project will advance the field of Nutritional Programming in relation to prevention of offspring obesity.

Progress Report
The third year of this project plan started in FY 2022. Under Objective 2, studies continued to determine maternal high fat diet-induced offspring phenotypes by testing changes in eating behavior, obesity, insulin resistance, inflammatory status, body weight, and epigenetic alterations. Tissue sample of placenta and F1 mice brain samples were collected to conduct RNAseq analysis. Objective 3 was also addressed and completed. In Objective 3, how maternal vegetable or probiotic supplementation alter placental growth and development to influence fetal growth have been initiated and completed. Results from all these studies will help formulate optimal maternal, paternal postnatal diet and exercise conditions for prevention of offspring obesity.

1. A maternal diet influences expression of brain function markers in offspring. Maternal malnutrition is a major cause of low offspring birth weight and adult-on set obesity and type 2 diabetes in offspring. However, whether maternal low-protein diet causes learning and memory deficits has not yet been determined. In a mouse model study, ARS scientists in Grand Forks, North Dakota, demonstrated that a maternal low protein diet decreases a brain growth factor called brain-derived neurotrophic factor. This factor is important for learning and memory. This study contributed to increasing our knowledge toward how a maternal malnutrition can have harmful effects on offspring brain function. This knowledge contributes to understanding the optimal maternal diet composition prior to conception in animal and eventually in human populations so that offspring brain dysfunction can be reduced.

2. Effects of a maternal high fat diet-induced fatty placenta and fetal weight reduction: Role of probiotic supplementation. Maternal obesity hinders fetal growth by restricting blood supply to the fetus. Probiotics play a beneficial role by reducing inflammation and by providing metabolic energy to host cells. Whether supplementing a maternal high fat diet with probiotic bacteria often found in yogurt helps to restore detrimental effects of maternal high fat diet is not known. ARS scientists in Grand Forks, North Dakota, tested the association between fat content of the placenta and fetal growth at the mid and late gestational periods in a rodent model and showed that probiotic supplementation provided beneficial effects in reducing placental tissue fat content at the mid-gestational period.

3. Effects of calcium transporter protein deactivation on regulation of placental and fetal body weight. Normal growth of placental tissue has been shown to be regulated by calcium levels within the placental cells. Other factors such as eating high fat diet alters placental tissue lipid concentration, nutrient transport to the fetus, and fetal development. An ARS scientist in Grand Forks, North Dakota, fed female mice lacking cellular calcium transport protein called TRPC1 high fat diet during pregnancy to test if genetic influence and high fat diet influence can have an additive effect. Results showed that limiting calcium transport within the placenta restricts fetal growth promotes fetal growth restriction and this adverse effect was exacerbated with a maternal high fat diet. These data demonstrate that both genetic background and maternal diet can have additive adverse effects on fetal growth.

4. Placental tissue lipidomic analysis of calcium channel protein TRPC1 gene knock out mouse fed maternal high fat diet. Placental function including oxygen delivery and nutrient transport are critical determinants of fetal growth. Transient receptor potential canonical channel 1 (TRPC1) is a calcium channel protein that controls calcium concentrations inside of cells. Using mice with TRPC1 protein knocked out, an ARS scientist in Grand Forks, North Dakota, demonstrated that elimination of TRPC1 protein promotes placental lipid accumulation, particularly in lipid family of sphingomyelins. These data demonstrate that accumulation of fat in the placental tissue due to lacking cellular calcium transport protein can have adverse effects on fetal growth.

5. Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous fat tissue beiging. It has been previously shown that maternal and paternal diets regulate offspring obesity and type 2 diabetes risk by altering methylation status of nuclear protein called Histone3 Lysine9 dimethyl transferase or G9a. This protein is also known for its regulation of metabolism and conversion of metabolically inactive fat cells into metabolically active beige color fat cells (beige adipocyte). Based on their previously published study of G9a regulation of fat tissue metabolism, an ARS scientist in Grand Forks, North Dakota, further investigated whether offspring exercise reduces obesity and type 2 diabetes risk caused by a maternal high fat diet. Results showed that postnatal high fat diet decreased beige color fat cell numbers and induced inhibitor of G9a protein. These results indicate that offspring high fat diet induced reduction in beige adipocyte is minimized by reducing G9a by offspring exercise via increasing G9a inhibitor expression.

Review Publications
Bukowski, M.R., Singh, B.B., Roemmich, J.N., Claycombe-Larson, K.J. 2022. Lipidomic analysis of TRPC1 Ca2+ permeable channel-knock out mouse demonstrates a vital role in placental tissue sphingolipid and triacylglycerol homeostasis under maternal high-fat diet. Frontiers in Endocrinology. 13. Article 854269.
Crouse, M.S., Caton, J.S., Claycombe-Larson, K.J., Diniz, W.J., Lindholm-Perry, A.K., Reynolds, L.P., Dahlen, C.R., Borowicz, P.P., Ward, A.K. 2022. Epigenetic modifier supplementation improves mitochondrial respiration growth rates and alters DNA methylation of bovine embryonic fibroblast cells cultured in divergent energy supply. Frontiers in Genetics. 13. Article 812764.
Zeng, H., Safratowich, B.D., Cheng, W., Larson, K.J., Briske Anderson, M.J. 2022. Deoxycholic acid modulates cell-junction gene expression and increases intestinal barrier dysfunction in Caco-2 cell monolayers. Molecular Nutrition and Food Research.
Larson, K.J., Bundy, A.N., Kuntz, T.M., Hur, J., Yeater, K.M., Casperson, S.L., Brunelle, D.C., Roemmich, J.N. 2022. Effect of maternal High Fat diet with vegetable substitution on fetal brain transcriptome. Journal of Nutritional Biochemistry.
Casperson, S.L., Jahns, L., Duke, S.E., Nelson, A.M., Appleton, K.M., Larson, K.J., Roemmich, J.N. 2022. Incorporating the dietary guidelines for Americans vegetable recommendations into the diet alters dietary intake patterns of other foods and improves diet quality in overweight adults and adults with overweight and obesity. Journal of the Academy of Nutrition and Dietetics.
Larson, K.J., Bundy, A.N., Lance, E.B., Casperson, S.L., Darland, D.C., Roemmich, J.N. 2021. Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J Mice. Journal of Nutritional Biochemistry.