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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

2017 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, the 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 expectation, 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. For objective 3, obese and lean human placental tissues were analyzed for an epigenetic alteration such as DNA methylation. Effects of maternal obesity on inflammatory and metabolic gene expression were determined. Of 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 these differentially methylated DNAs are genes linked to development of type 2 diabetes mellitus. Of these genes, one particular regulator has been found to help preserving normal function of placenta in obese humans. Subordinate Studies: 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 mouse model of high saturated fat diet-induced obesity, beneficial probiotic were supplemented to the high fat diet. A maternal high fat diet induced maternal obesity and increased placental inflammation. This study is expected to be completed by end of year 2017. As placental inflammation cause placental cell function alteration, we expect to observe compromised placental function and fetal growth. Adipose tissue energy metabolism is regulated by mitochondrial intracellular calcium levels. Using approximately 32 mice lacking calcium transporter protein, we fed these mice high saturated fed and/or exercised them for 3 months. We determined whether an absence of calcium transporter protein regulate 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 TRPC1 promotes exercise-induced protection against high-fat diet-induced obesity and type II diabetes. Prenatal exposure to a maternal malnutrition, particularly low-protein diet, has been known to cause learning and memory deficits. Using mouse model of maternal low protein and postnatal high saturated fat diets, we determined whether offspring were at risk for obesity and dysregulation of brain growth factor expression. We demonstrate that a maternal low protein diet causes a decrease in brain growth factor called the brain-derived neurotrophic factor, a factor important for learning and memory. Our study is the first to determine the impact of a maternal LP diet on the expression of BDNF in the brains of the neonatal animals.


4. Accomplishments
1. Effect of maternal and postnatal high fat diets and offspring exercise on offspring beige adipocyte numbers and metabolic function. ARS scientists in Grand Forks, North Dakota showed that obesity in offspring is determined, in part, by a decreased numbers of beige fat cells, the more metabolically active type of fat. The offspring could not make as many beige fat cells if the maternal and postnatal maternal diets contained high amounts of fat. Exercise by the offspring resulted in reversing the harmful effects of 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 healthy diet and paternal exercise on the offspring’s risk for type 2 diabetes mellitus and on obesity risk via the number of beige adipocytes has not yet been determined. ARS scientists in Grand Forks, North Dakota showed that a paternal high-fat diet and exercise changed offspring fat tissue weight without changing the total numbers of beige adipocytes. 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 optimal paternal diet composition and physical activity levels prior to conception to reduce offspring type 2 diabetes risk.

3. 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 working with collaborators from the University of North Dakota used maternal 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 a maternal malnutrition can have harmful effects on offspring brain function.


Review Publications
Xie, L., Zhang, K., Rasmussen, D., Wang, J., Wu, D., Roemmich, J.N., Bundy, A.N., Johnson, W., Larson, K.J. 2017. Effects of prenatal low protein and postnatal high fat diets on visceral adipose tissue macrophage phenotypes and IL-6 expression in Sprague Dawley rat offspring. Journal of Nutrition. doi: 10.1371/journal.pone.0169581.

Dhasarathy, A., Roemmich, J.N., Larson, K.J. 2017. Influence of maternal obesity, diet and exercise on epigenetic regulation of adipocytes. Molecular Aspects of Medicine. 54:37-49.

Dekrey, E.E., Roemmich, J.N., Larson, K.J. 2016. Maternal low protein diet leads to placental angiogenic compensation via dysregulated M1/M2 macrophages and TNFa expression in Sprague-Dawley rats. Journal of Reproductive Immunology. 118:9-17.

Marwarha, G., Larson, K.J., Schommer, J., Ghribi, O. 2017. Maternal low protein diet decreases brain-derived neurotrophic factor expression in the brains of the neonatal rat offspring. Journal of Nutritional Biochemistry. 45:54-66.

Marwarha, G., Larson, K.J., Schommer, J., Collins, D., Ghribi, O. 2017. Palmitate-induced ER stress and subsequent C 1 HOP activation attenuates leptin and IGF1expression in the brain. Cellular Signaling. 28(11):1789-1805.