Location: Healthy Body Weight Research2016 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 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.
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 1 of maternal diet influence on regulation of adipose tissue and muscle energy metabolism in the offspring (animal model study), the levels of beige adipocyte markers from subcutaneous and visceral adipose tissues and skeletal muscle tissues were measured. A maternal HF diet was discovered to be a major determinant of offspring adiposity and associated risk for type 2 diabetes mellitus in that a healthy diet and exercise in the F1 generation did not improve risk for type 2 diabetes mellitus if the maternal diet was high in fat. Testing of beige adipocyte markers and numbers of beige adipocytes paralleled these observations. For objective 3 regarding maternal diet influences on regulation of human placenta and fetal tissue metabolism, approximately 170 different regions of human genes in placenta tissues were found to be differentially methylated in non-overweight mothers compared to obese mothers. Some of these differentially methylated DNAs are genes linked to development of type 2 diabetes mellitus. Assessments of the effects of a high-fat diet and exercise by the father on adipose tissue energy metabolism in the offspring (Objective 1: hypothesis 1b) was initiated in FY 2016. For this mouse experiment, the first cohort of the F1 generation has been bred and the first cohort of the project will be finished by the end of FY 2017. Subordinate Studies: The evaluation of adipose tissue energy metabolism (Objective 1) requires suitable markers to gauge the expression of key genes. The validity of cellular markers of beigeing was determined so that the degree of beigeing taking place in white adipose tissue of the offspring of male and female mice fed high-fat diets can be reliably examined. This work was published in the journal Nutrition and Metabolism. It was determined that female and male offspring adipose tissue energy metabolism is affected to different extents by feeding a high-fat diet to the mothers. This evidence implicates the sex hormones in the modulation of adipose tissue energy metabolism. As a result of these findings, research was initiated regarding the effects of testosterone and estradiol on the regulation of the expression of uncoupling protein-1 in beige adipocytes.
1. Effects of maternal diet on offspring beige adipocyte number and metabolic function. ARS scientists in Grand Forks, North Dakota showed that obesity in offspring is determined, in part, by decreased numbers of beige fat cells that are metabolically more active than white fat cells. The offspring could not make beige fat if the maternal diet contained a low amount of protein. Offspring born from normal level of protein in their diet were able make beige fat cells.
2. Physiological condition dependent changes in beige adipocyte markers. The best markers to evaluate beigeing of white adipose tissue and how their use is affected by different physiological situations have not been well studied. ARS scientists in Grand Forks, North Dakota published research on beige markers in white adipose tissue of male mice outlining several limitations of widely used markers and identifying those that produce the best results. This knowledge will allow researchers in nutrition and other areas to more accurately gauge the extent of beigeing in animal models in response to experimental treatments.
Claycombe, K.J., Dekrey, E.E., Garcia Garcia, R.A., Johnson, W.T., Uthus, E., Roemmich, J.N. 2016. Decreased beige adipocyte number and mitochondrial respiration coincide with increased histone methyl transferase (G9a) and reduced FGF21 gene expression in Sprague Dawley rats fed prenatal low protein and postnatal high fat diets. Journal of Nutritional Biochemistry. 31:133-121.