Location: Healthy Body Weight Research
2015 Annual Report
Objectives
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 mechanism by which replacement of high fat maternal diet with omega-3 fatty acids have on the regulation of adipose tissue and muscle energy metabolism in the offspring.
Objective 3: 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.
Approach
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.
Progress Report
During first 9 mo of FY 2015, as carry-over from the previous project plan, considerable progress was made in identifying the mechanism of maternal low protein diet on energy metabolism that contributes to offspring obesity and insulin resistance. Using a rat model, the project team conducted several studies to determine how prenatal (LP) and postnatal high fat (HF) diets influence offspring muscle energy oxidation and brown adipose tissue thermogenesis. These studies have been published in Journal of Nutritional Biochemistry. The final study in this series addressed whether maternal LP and postnatal HF diet-induced reduction in subcutaneous adipose tissue mitochondria number and oxidative respiration is mediated via decreased beige adipocytes. Collectively, between years 2013-2015, 6 original research and review papers have been published from this research project’s studies and in the area of maternal diet and epigenetic regulations.
The new project plan that started FY 2015 extended our previous work in animal studies and opened a new area of research to translate our animal work to human studies. For the animal studies, ARS scientists are determining whether maternal and postnatal diets, hormonal factors, and exercise alter adipose tissue metabolism, particularly whether these factors alter the formation of beige adipocytes that are rich in fat oxidizing mitochondria. Results from these studies will help formulate optimal maternal, postnatal diet and exercise conditions for prevention of offspring obesity. Other animal studies focus on immune cell regulation of inflammation in placental tissue. For this work, maternal diet-induced changes in T lymphocyte cells that are important in inflammation and energy homeostasis are being studied. Results of this study will help to formulate maternal diet conditions optimal for reducing placental inflammation and normal placental tissue growth.
Accomplishments
1. Markers of beiging in white adipose tissue. There is much interest in beige adipocytes because they expend more energy and secrete different messengers than white adipocytes. Under some conditions, beige adipocytes can be developed from white adipocytes. However, there is uncertainty as to the best markers to evaluate when white adipose tissue takes on a beige characteristic in response to dietary or other environmental stimuli. ARS scientists in Grand Forks, North Dakota, performed a systematic evaluation of proposed markers of adipose tissue beiging and defined the best set of markers to monitor this process. This knowledge will allow the evaluation of the changes in the abundance of beige adipocytes in response to exercise, or dietary fats.
2. Gender specific effects of exercise on maternal- or postnatal HF diets on offspring body composition. A maternal high-fat diet increases, while exercise reduces offspring obesity in mice. ARS scientists in Grand Forks, North Dakota, demonstrated that exercising female offspring reduces fat tissue weight regardless of whether mom ate a high-fat or normal fat diet when pregnant. However, the protective effect of exercise on offspring adiposity was not as strong in males. These data help to explain how the maternal diet and offspring exercise affect offspring fat tissue weight differently in male and female offspring. Data generated from these studies will help formulate optimal maternal diet and postnatal exercise conditions to prevent offspring obesity for each sex.
Review Publications
Zeng, H., Claycombe, K.J., Reindl, K.M. 2015. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation. Journal of Nutritional Biochemistry. 26:1022-1028.
Claycombe, K.J., Dekrey, E.E., Roemmich, J.N., Ghribi, O., Rhen, T. 2015. Maternal low protein diet causes body weight loss in male, neonate Sprague-Dawley rats involving UCP-1 mediated thermogenesis. Journal of Nutritional Biochemistry. 26(7):729-735.
Claycombe, K.J., Brissette, C., Ghibri, O. 2015. Epigenetics of inflammation, maternal infection and nutrition. Journal of Nutrition. 145(5):1109S-15S.
Stephensen, C.B., Dawson, H.D., Claycombe, K.J. 2015. Impact of nutrition on immune function and the inflammatory response. Journal of Nutrition. 145(5):1039S-1108S. DOI: 10.3945/jn.114.194571.
Claycombe, K.J., Roemmich, J.N., Johnson, L., Dekrey, E.E., Johnson, W.T. 2015. Skeletal muscle Sirt3 expression and mitochondrial respiration are regulated by a prenatal low protein diet. Journal of Nutritional Biochemistry. 26(2):184-189.
