Location: Obesity and Metabolism Research
2019 Annual Report
Objectives
The following research project addresses a key unmet need of the USDA Human
Nutrition Program, namely to test the metabolic impact of the Dietary Guidelines
for Americans (DGA) --which has immediate nutrition policy implications. To
achieve this goal, project scientists have designed an interdisciplinary effort
leveraging tools from analytical chemistry, biochemistry, clinical nutrition,
endocrinology, exercise biology, genetics, molecular biology, physiology, and
psychological/CNS-based assessments - applying cutting edge phenotyping tools
alongside complementary basic research experiments.
Objective 1: Determine if achieving and maintaining a healthy body weight is the
key health promoting recommendation of the Dietary Guidelines for Americans (DGA).
Sub-objective 1A: Determine if achieving and maintaining a healthy body weight
improves cardiometabolic risk in persons at-risk for metabolic disease.
Sub-objective 1B: Determine if chronic stress, stress system responsiveness, and
diet quality interact to influence metabolic responses and if these responses can
be sustained over time.
Sub-objective 1C: Determine the eating behavior characteristics, including dietary
restraint, food cravings and preferences, motivation for food choice, and satiety
response to a meal challenge to evaluate a) how diet interventions affect these
variables b) which behavioral variables are associated with adherence to prescribed
diet during the fully controlled interventions (mos 1 & 2) and during the partially
controlled interventions (mos 3-6) c) and body weight changes during the follow-up
period.
Sub-objective 1D: Determine how weight loss and diet interact to influence
lipoprotein particle metabolomic structure and their association with
cardiometabolic risk factors.
Objective 2: Identify hepatic gene polymorphisms associated with metabolic
response to diets. This objective complements and integrates with Objective 1,
which systematically tests the effect of the DGA. Objective 2 studies are designed
to identify genetic sources of variation and their impact on metabolism in response
to diet using a population of mice with defined genetic diversity to answer the
following sub-objectives:
Sub-objective 2A: Identify gene-diet interactions affecting adiposity and hepatic
fat accumulation.
Sub-objective 2B: Identify changes in gut microbiome composition associated with
resistance to weight loss.
Sub-objective 2C: Determine how atherogenic risk mechanisms alter lipoprotein particle lipidomic structure in cardiometabolic disease models.
Objective 3: Develop Reference Values for mineral and vitamin concentrations in human milk, which will improve estimates of recommended nutrient intakes for breastfeeding infants and their mothers.
Approach
Objective 1 Hypotheses: 1A1: Consuming a DGA diet pattern for 8 wk will improve cardiometabolic risk factors, primarily insulin sensitivity and lipid profiles, compared to a typical American diet (TAD); 1A2: Cardiometabolic improvements resulting from the DGA diet will be greater in overweight/obese women when energy intake is restricted to result in weight loss; 1B: Phenotypic differences in psychological stress will partly explain variation in metabolic responses to a healthy diet; 1C1: Hunger, circulating ghrelin, and snack selection following a meal challenge will be greater with energy-restricted diets; 1C2: Adherence to the DGA diets will be better than adherence to the TAD diets when controlled for eating behavior, cognitive function, and subjective satiety; 1C3: Body weight changes in the follow-up period will associate with endocannabinoid tone, craving, and increased palatable food intake independent of intervention group; 1D1: Weight loss-induced metabolomic changes in plasma particles will decrease LDL region pro-atherogenic character, while increasing HDL anti-atherogenic character; 1D2: Diets rich in fruits, vegetables, and omega-3 fatty acids will reduce the 8 wk concentrations of non-enzymatically generated oxygenated lipids in LDL region lipoproteins.
Objective 2 Hypotheses: 2A: Reduction in adiposity associated with dietary change is due to both genetic and dietary interactions; 2B: Gut microbial diversity will affect the weight loss response in a genetically diverse mouse population; 2C: Dietary manipulations will differentially change the lipoprotein oxylipins and ceramide composition in atherosclerosis prone vs. resistant cardiometabolic disease mouse models.
A Randomized Control Trial will address hypotheses under Objective 1. This trial will be an intervention with human volunteers randomized to one of four parallel diet groups: 1. participants will consume a diet based on the Dietary Guidelines for Americans (DGA) and maintain energy balance; 2. participants will consume a control diet based on the typical American diet (TAD) and maintain energy balance; 3. participants will consume a DGA diet, restricted in calories to stimulate body weight loss; and 4. participants will consume a TAD, restricted in calories in order to stimulate body weight loss.
A complementary mouse experiment will address Objective 2 hypotheses. This study will use diets formulated to match the diet types used in Objective 1 for the TAD and DGA. Four experimental groups will be tested: Ad libitum DGA diet; energy restricted DGA diet; ad libitum TAD diet; and energy restricted TAD diet. This study utilizes a systems genetic approach using genetic reference panels to assess gene x diet interactions that affect both the susceptibility to obesity and the resistance to weight loss.
Objective 3 Hypothesis: Reference Values for vitamins and minerals in human milk can be established by measuring the range of concentrations in milk from well-nourished women who are not consuming additional micronutrients through supplements or fortified foods.
Progress Report
This report documents progress for project 2032-51530-025-00D, which began in March, 2019 and continues research from project 2032-51530-022-00D, "Improving Public Health by Understanding Diversity in Diet, Body, and Brain Interactions."
Under Objective 1, researchers at Davis, California, began planning and developing the intervention diets, staffing the study, and preparing the Institutional Review Board application for conducting human studies.
Under Objective 2, researchers began planning and developing the mouse study diets and preparing the Institutional Animal Care and Use Committee (IACUC) application for conducting the mouse studies.
Under Objective 3, researchers completed human milk sample collection from: 50 to 100 percent of study test visit one (at 2-3 days postpartum); 27 to 100 percent of study test visit two (1 to 3.5 months postpartum); 16 to 80 percent of study test visit three (3.5 to 6 months postpartum); and 7 to 60 percent of study test visit four (at 6 to 8.5 months postpartum. In addition to breast milk samples, blood is drawn from the mother and infant for assessment of nutritional status and hormones. Saliva is sampled from the mother and infant for assessment of milk volume using a deuterium dosing method. Feces from the mothers and infants is sampled for evaluation of the fecal microbiome. The first blood, saliva, and fecal samples arrived at the USDA, ARS facility in Davis, California, where the team developed all of the methods necessary for efficient, rapid analysis of nutrients in human milk. A data base was finalized. Researchers submitted a final request for Supplemental Funding in July, 2019 that would enable the addition of more analyses to existing samples (fecal microbiome and metagenome, milk hormones, human milk oligosaccharides, and maternal genetics). In 2019, the investigators validated the use of Biocrates plates for measuring hundreds of metabolites in milk; these plates are normally intended for the analysis of the plasma metabolome.
Accomplishments
1. Vitamin B12 added as a fortificant to flour retains high bioavailability when baked in bread. International agencies now recommend that wheat flour be fortified with vitamin B12 in regions where intake of the vitamin is low due to inadequate intake of animal source foods. ARS investigators in Davis, California, conducted a pilot study to determine if vitamin B12 added to flour then baked in bread would still be available and well absorbed by the elderly. The novel approach was to label the B12 with an extremely low, harmless, dose of 14-C, add it to flour, bake it in bread, feed it to five elderly study volunteers, and trace its appearance in plasma and urine using accelerator mass spectrometry. Approximately 50 percent of the vitamin in bread was absorbed, a similar amount to that found in foods such as meat and fish. Adding B12 to wheat flour used for baking is an excellent way to improve B12 status of populations.
2. A targeted metabolomics kit was validated for measuring the metabolomic profile of human milk. Human-milk-targeted metabolomics analysis offers novel insights into milk composition and relationships with maternal and infant phenotypes and nutritional status. The Biocrates AbsoluteIDQ® p180 kit was developed for rapid measurement of 180 compounds in human serum but had not been validated for human milk, so ARS scientists in Davis, California, validated the method on milk using mass spectrometry. To demonstrate the potential application of the method, milk from apparently healthy Bangladeshi mothers and those with stunted infants was analyzed and 123 of the possible 188 metabolites were detected with good recoveries, using new internal standards and adjusted calibrator levels to adjust to concentration ranges in milk. Milk consumed by stunted infants versus that from mothers was lower in 6 amino acids/biogenic amines, but higher in isovalerylcarnitine, two phospholipids, and one sphingomyelin, and associations among milk metabolites differed between groups. The ability to measure 123 metabolites rapidly in a small sample of milk presents a new opportunity for researchers to understand factors affecting the composition and mechanisms of action of human milk.
Review Publications
Hieronimus, B., Griffen, S.C., Keim, N.L., Bremer, A.A., Berglund, L., Nakajima, K., Havel, P.J., Stanhope, K. 2019. Effects of fructose or glucose on circulating apoCIII and triglyceride and cholesterol content of lipoprotein subfractions in humans. Journal of Clinical Medicine. 8(7):913. https://doi.org/10.3390/jcm8070913.
Stewart, C.P., Dewey, K.G., Lin, A., Pickering, A.J., Byrd, K.A., Jannat, K., Ali, S., Rao, G., Dentz, H.N., Kiprotich, M., Arnold, C.D., Arnold, B.F., Allen, L.H., Shahab-Ferdows, S., Ercumen, A., Grembi, J.A., Naser, A.M., Rahman, M., Unicomb, L., Colford, J.M., Luby, S.P., Null, C. 2019. Effects of lipid-based nutrient supplements and infant and young child feeding counseling with or without improved water, sanitation, and hygiene (WASH) on anemia and micronutrient status: results from two cluster randomized trials in Kenya and Bangladesh. American Journal of Clinical Nutrition. 109(1):148-164. https://doi.org/10.1093/ajcn/nqy239.
Golden, C.D., Borgerson, C., Rice, B.L., Allen, L.H., Anjaranirina, J.G., Barrett, C.B., Boateng, G., Gephart, J.A., Hampel, D., Hartl, D.L., Knippenberg, E., Myers, S.S., Ralalason, D.H., Ramihantaniarivo, H., Randriamady, H.J., Shahab-Ferdows, S., Vaitla, B., Volkman, S.K., Vonona, M.A. 2019. Cohort description of the Madagascar health and environmental research-antongil (MAHERY-Antongil) study in Madagascar. Frontiers in Nutrition. 6:109. https://doi.org/10.3389/fnut.2019.00109.
Gaitan, A.V., Wood, J.T., Solomons, N.W., Donohue, J.A., Ji, L., Liu, Y., Nikas, S.P., Zhang, F., Allen, L.H., Makriyannis, A., Lammi-Keefe, C.J. 2019. Endocannabinoid metabolome characterization of milk from Guatemalan women living in the Western Highlands. Current Developments in Nutrition. 3(6):1-6. https://doi.org/10.1093/cdn/nzz018.
Hampel, D., Shahab-Ferdows, S., Hossain, M., Islam, M., Ahmed, T., Allen, L.H. 2019. Validation and application of Biocrates AbsoluteIDQ® p180 targeted metabolomics kit using human milk. Nutrients. 11(8):1733. https://doi.org/10.3390/nu11081733.
Daniels, L., Gibson, R.S., Diana, A., Haszard, J.J., Rahmannia, S., Luftimas, D.E., Hambel, D., Shahab-Ferdows, S., Reid, M., Melo, L., Lamers, Y., Allen, L.H., Houghton, L.A. 2019. Micronutrient intakes of lactating mothers and their association with breast milk concentrations and micronutrient adequacy of exclusively breastfed Indonesian infants. American Journal of Clinical Nutrition. 110(2):391-400. https://doi.org/10.1093/ajcn/nqz047.
Anaya-Loyola, M., Brito, A., Villalpando, S., Allen, L.H. 2019. Prevalence of low serum vitamin B12 in Mexican children and women: results from the first National Nutrition Survey (1999) as a basis for interventions and progress. International Journal for Vitamin and Nutrition Research. https://doi.org/10.1024/0300-9831/a000579.
Rajamani, A., Borkowski, K., Akre, S., Fernandez, A., Newman, J.W., Simon, S.I., Passerini, A.G. 2019. Oxylipins in triglyceride-rich lipoproteins of dyslipidemic subjects promote endothelial inflammation following a high fat meal. Scientific Reports. 9:8655. https://doi.org/10.1038/s41598-019-45005-5.
Gladine, C., Ostermann, A.I., Newman, J.W., Schebb, N.H. 2019. MS-based targeted metabolomics of eicosanoids and other oxylipins: analytical and inter-individual variabilities. Journal of Free Radical Biology and Medicine. 144:72-89. https://doi.org/10.1016/j.freeradbiomed.2019.05.012.
