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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 #426891

Research Project: Biology of Obesity Prevention

Location: Healthy Body Weight Research

2018 Annual Report


1a. Objectives (from AD-416):
Obesity and obesity risk are perpetuated across generations. DNA alterations that occur in utero are capable of inducing changes in gene expression that are sustained throughout the life span. Understanding maternal factors that establish an embryonic and fetal environment that promote obesigenic epigenetic changes is vital to developing maternal health habits that will reduce obesity risk across generations. The overarching goal of this project is to determine the mechanisms by which the maternal diet, maternal obesity, and maternal aerobic exercise modify the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes in the subcutaneous, visceral and intermuscular (skeletal muscle) fat depot of offspring. The project will utilize animal models and translation to a human study to investigate epigenetic transmission of beige adipocyte differentiation and lipid metabolism as causes of obesity risk across generations. Objective 1: Determine the mechanisms by which high fat in the maternal diet and a high fat diet and exercise in the offspring influence the regulation of adipose tissue and muscle energy metabolism in the offspring. Objective 2: Determine the effects of human maternal obesity and exercise participation during pregnancy on DNA methylation, energy metabolism and adipocyte tissue regulation of women and their infants.


1b. Approach (from AD-416):
The maternal consumption of excess food energy leading to maternal obesity contributes to the subsequent development of obesity in offspring. This phenomenon, in part, involves the epigenetic transmission of obesity risk across generations. The overarching hypothesis of this proposal is that a maternal high fat diet and maternal obesity increase the risk of development of obesity in offspring by reducing the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes in the offspring. To identify anti-obesity strategies, this project will first determine mechanisms of how excess maternal energy intake via high fat diets contributes to programming of epigenetically imprinted genes that control oxidation of lipids in subcutaneous fat and intermuscular (skeletal muscle) fat depots of offspring, thus contributing to offspring obesity. Effects of interventions, aerobic exercise and replacement of high dietary saturated fat with n-3 polyunsaturated fatty acids (n3-PUFAs), will be tested to determine whether these interventions have beneficial effects on reducing offspring obesity by promoting the conversion of white adipocytes into more mitochondrial enriched and metabolically active beige adipocytes. The common focus across all studies is obesity-associated increases in insulin and insulin-like growth factor 1 and 2 concentrations and their role in modulating differentiation of beige adipocytes via activation of a key transcription factor involved in beiging, PR domain containing 16 (PRDM16). The main hypothesis is that maternal obesity and a high saturated fat diet induce offspring obesity and type 2 diabetes mellitus (T2DM) by inhibiting PRDM16 activation and beige adipocyte differentiation resulting in decreased lipid oxidation and increased fat storage. The second hypothesis is that exercise and replacement of saturated fat diet partially with n-3 PUFA decrease IGF1 and 2 and insulin to restore PRDM16 activation and beige adipocyte differentiation. This project will test these hypotheses, using a combination of animal model studies and a pilot human intervention trial. These results will inform diet and exercise guidelines for pregnant women to the end of optimizing the long-term health of their children.


3. Progress Report:
For Objective 1a, regarding the influence of maternal and postnatal high fat diets on regulation of adipose tissue and muscle energy metabolism in F1 offspring, expression levels of beige adipocyte markers from subcutaneous and visceral adipose tissues and skeletal muscle tissues were measured. Maternal and postnatal high fat diets were discovered to be important determinants of F1 offspring risk for adiposity and insulin resistance. However, consumption of a normal fat diet or engaging in exercise by the F1 offspring reduced the pre-programmed risk for insulin resistance. Consumption of a normal fat diet or engaging in exercise by the F1 offspring also increased the expression of beige adipocyte markers and numbers of beige adipocytes. The study was completed. One manuscript is being prepared for submission. For Objective 1b, a mouse model study of the effects of a paternal high-fat diet and exercise on adipose tissue weight and energy metabolism in the F1 offspring was initiated and completed. Effects of a paternal high fat diet and exercise and postnatal high fat diet on offspring obesity, beige adipocyte formation, and type 2 diabetes mellitus risk were determined. Opposite to our hypothesis, a paternal high fat diet reduced offspring adiposity, but it did not improve offspring insulin resistance. However, paternal exercise enhanced offspring skeletal muscle uptake of blood glucose by enhancing the insulin signaling pathway resulting reduced offspring type 2 diabetes mellitus risk. One manuscript is published in the Journal Nutritional Biochemistry in 2018. For Objective 3, human placental tissues from obese and lean mothers were analyzed for an epigenetic alteration such as DNA methylation. Effects of maternal obesity on inflammatory and metabolic gene expression were determined. Approximately 170 different regions of human genes in placenta tissues were found to be differentially methylated in lean mothers compared to obese mothers. Some of this differentially methylated DNA are genes linked to development of type 2 diabetes mellitus. Of these genes, one particular regulator helps to preserve normal function of the placenta. This gene showed epigenetic changes in the obese mothers. One manuscript is being prepared for submission. For Objective 3, maternal obesity and placental microbiome studies were initiated in FY2017. The focus was to test the association between placental inflammation and composition of the placental microbiome. Using a mouse model of high saturated fat diet-induced obesity, beneficial probiotics were supplemented to the high fat diet. A maternal high fat diet induced maternal obesity and increased placental inflammation. Placenta length, width, and weight as well as fetal weights were decreased in the maternal high fat diet fed group. Probiotic supplementation reversed the high fat diet-induced reduction in the placental weight and reduced placental inflammation. Adipose tissue energy metabolism is regulated by mitochondrial intracellular calcium levels. A mouse model that lacked a calcium transporter protein was fed high saturated fed and/or exercised for 3 months. We determined whether an absence of calcium transporter protein regulates adiposity and risk for type 2 diabetes mellitus. We showed that calcium transport plays an important role in the regulation of body weight and adiposity and that loss of one type of calcium entry into cells promotes exercise-induced protection against high-fat diet-induced obesity and type II diabetes. One manuscript is published in the Journal of Biochemistry.


4. Accomplishments
1. The Effect of maternal and postnatal high fat diets and offspring exercise on beige adipocyte function. ARS scientists in Grand Forks, North Dakota showed that obesity in offspring is determined, in part, by a decreased number of beige fat cells, the more metabolically active type of fat. The offspring did not make as many beige fat cells if the maternal and postnatal diets contained high amounts of fat. Exercise by the offspring resulted in reversing the harmful effects of a maternal and postnatal high fat diet by increasing the number of beige fat cells.

2. Paternal diet and exercise changes the skeletal muscle insulin signaling pathway in offspring. A potential beneficial effect of a paternal (father’s) healthy diet and paternal exercise may be to reduce risk for type 2 diabetes mellitus and obesity in the next generation. ARS scientists in Grand Forks, North Dakota showed that a paternal high fat diet reduced offspring adipose tissue mass while paternal exercise enhanced offspring skeletal muscle uptake of blood glucose by enhancing insulin signaling, resulting in reduced risk of type 2 diabetes mellitus. This knowledge will contribute to understanding the optimal paternal diet composition and physical activity levels prior to conception so that offspring type 2 diabetes risk can be reduced.

3. A maternal diet influences expression of brain function markers in offspring. How maternal malnutrition, particularly a low-protein diet, causes learning and memory deficits has not yet been determined. ARS scientists in Grand Forks, North Dakota, working with collaborators from the University of North Dakota used a maternal (mother’s) low protein diet in a mouse model to demonstrate that a maternal low protein diet decreases a brain growth factor called the brain-derived neurotrophic factor. This factor is important for learning and memory. This study contributed to increasing our knowledge toward how maternal malnutrition can have harmful effects on offspring brain function.

4. Effects of a maternal high fat diet-induced fatty placenta and fetal weight reduction: Role of probiotic supplementation. Maternal (mother’s) obesity hinders fetal growth by restricting blood supply to the fetus. Whether supplementing maternal high fat diet with probiotic bacteria often found in yogurt can help restore detrimental effects of maternal high fat diet is not known. ARS scientists at Grand Forks, North Dakota tested the association between the fat content of the placenta and fetal growth at the mid and late gestational period and showed that probiotic supplementation provides beneficial effects in reducing placental tissue fat content at the mid-gestational period. Results of this research will serve as a proxy for understanding the biology of humans and considerations of standards for prenatal care.

5. Effects of calcium transporter protein deactivation on regulation of body weight under exercised conditions. Adipose tissue energy metabolism is regulated in part by calcium levels in body cells. It is not known whether lacking calcium transporter protein (TRPC1) in mice results in increased risks for development of obesity and type 2 diabetes mellitus. Using mice lacking calcium transporter protein, ARS scientists at the Grand Forks, North Dakota demonstrated that calcium transport plays an important role in the regulation of body weight and adiposity and that loss of TRPC1 promotes exercise-induced protection against high-fat diet-induced obesity and type II diabetes. The scientific publications produced by this project will contribute to increasing our basic science knowledge on how cellular calcium levels contribute to risks for development of obesity and type 2 diabetes mellitus by controlling fat cell metabolism. One manuscript was published in the Journal of Biochemistry in December, 2017.


Review Publications
Jahns, L.A., Conrad, Z.S., Johnson, L., Whigham, L.D., Wu, D., Larson, K.J. 2018. A diet high in carotenoid-rich vegetables and fruits modifies plasma Interferon alpha-2, Macrophage inflammatory protein-1 beta and Tumor necrosis factor-alpha in healthy individuals. Nutrition Research. 52:98-104. https://doi.org/10.1016/j.nutres.2018.02.005.

Krout, D.P., Roemmich, J.N., Garcia Garcia, R.A., Bundy, A.N., Yan, L., Larson, K.J. 2018. Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling. Journal of Nutritional Biochemistry. 57:35-44. https://doi.org/10.1016/j.jnutbio.2018.03.013.

Krout, D.P., Schaar, A., Sun, Y., Sukumaran, P., Roemmich, J.N., Singh, B.B., Larson, K.J. 2017. The TRPC1 CA2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes. Journal of Biological Chemistry. 292(50):20799-20807. https://doi.org/10.1074/jbc.M117.809954.