Location: Obesity and Metabolism Research2011 Annual Report
1a. Objectives (from AD-416)
The overall goal of the proposed research is to identify foods, nutrients, and food components that promote health and prevent disease in at-risk populations; where possible diet-gene interactions will be explored. Over the next 5 years we will focus on the following objectives: OBJECTIVE 1: Determine the effects of specific foods, fortified foods, and nutrients on bone health of at-risk population groups. Sub-objective 1.A. Determine the effects of carbonated beverages and milk on calcium kinetics and calcium efflux from the skeleton of women and girls. Sub-objective 1.B. Determine the effects of vitamin B12 deficiency on markers of calcium kinetics, bone health, and calcium metabolism in postmenopausal women. OBJECTIVE 2: Investigate vitamin B12 and zinc intestinal absorption and metabolism in at-risk populations. Sub-objective 2.A. Determine the absorption of 14C-vitamin B12 from fortified foods in elderly with gastric atrophy and H. pylori infection, pre- and post H. pylori treatment. Sub-objective 2.B. Determine the impact of SNPs in a major Zn uptake gene (ZIP4) on dietary Zn absorption using ZIP4-expressing cell lines. OBJECTIVE 3. Investigate the effect of Zn supplementation on the development of prostate cancer, a cancer common in African-Americans, using a mouse prostate cancer model (TRAMP).
1b. Approach (from AD-416)
The overall goal is to identify foods, nutrients, and food components that promote health and prevent disease in at-risk populations and to identify diet gene interactions where possible. To achieve this goal, human studies will be conducted investigating the effects of carbonated beverages and milk on calcium kinetics and calcium efflux from the skeleton of women and girls; effects of vitamin B12 deficiency on markers of calcium kinetics, bone health, and calcium metabolism in postmenopausal women; and determine the absorption of 14C-vitamin B12 from fortified foods in elderly with gastric atrophy and H. pylori infection, pre- and post H. pylori treatment. Animal models will be used to investigate the impact of SNPs in a major Zn uptake gene (ZIP4) on dietary Zn absorption using ZIP4-expressing cell lines and to investigate the effect of Zn supplementation on the development of prostate cancer, common in African-American men. There is a need to devise effective nutrition interventions to prevent the progress of chronic disease in at-risk populations. Replacing: 5306-51520-006-00D (Van Loan, Allen) and 5306-51530-014-00D (Huang). Formerly 5306-51520-006-00D (4/09).
3. Progress Report
Objective 1.A. The project on the effect of dairy foods on fat and weight loss has been completed, primary manuscript has been accepted for publication. Secondary papers are in preparation. New project to examine the effect of milk versus supplements on calcium efflux from bone has been initiated. Required radiation and human subjects approval has been obtained. Recruitment started in October, 9 women have been enrolled, dosed and are on the stabilization period. Intervention will begin in August, and continue through 2012. Funding has been obtained from the Dairy Research Institute and Dairy Council of California. Sub-objective 1.B. Baseline 41Ca dosing and supplementation of 9 women has been completed. Recruitment has been difficult because a selection criterion is low serum vitamin B12 and few volunteers met this requirement. To obtain preliminary data for a grant proposal, some urine samples from three women were analyzed for 41Ca by accelerator mass spectrometry (AMS) at Lawrence Livermore National Lab. A grant proposal was submitted to the Department of Defense to obtain additional funding, primarily for the cost of the AMS measures ($300 per time point) and to expand the study to a larger B12 supplementation trial. The proposal was not funded and is being resubmitted elsewhere. Additional funding is critical to support cost of the AMS analyses on stored samples. Sub-objective 2.A. This research uses a novel approach for measuring vitamin B12 absorption from a very low dose 14C-B12 produced in bacteria. The labeled B12 was added to bread dough prior to baking and used to prepare fortified bread. The protocol worked well in the 5 healthy control subjects completed so far. Recruiting volunteers with gastric atrophy has been unsuccessful even after efforts to contact local physicians, work with the UC Davis Medical School, and search 4000 Electronic Medical records to identify potential subjects based on medical information. We will therefore substitute subjects on proton pump inhibitors who also have low gastric acid production. The IRB was recently approved and B12 absorption form fortified bread will be measured in 5 such subjects in FY2012. In addition with funds from the Egg Nutrition Council we used a similar protocol to measure 14C-B12 absorption from chicken eggs labeled in vivo. In a group of 10 subjects we showed bioavailability of B12 from eggs to be good (around 30%). A final report has been submitted to the Egg Nutrition Council and a manuscript is in preparation. Objective 3: Twenty-two percent of TRAMP mice (two out of nine) fed a semi-purified diet containing 15 mg zinc/kg diet at four weeks of age developed prostate cancer at 28 weeks of age which was significantly lower than that of TRAMP mice fed a regular chow diet containing 80 mg zinc/kg diet. In addition, none of the two TRAMP mice with prostate tumor had tumor metastasised to the draining lymph nodes. This is the first demonstration in an animal model with direct evidence that cellular zinc homeostasis is associated with prostate cancer development.
1. Dairy foods minimize bone loss during energy restriction in overweight and obese adults. Researchers at the Western Human Research Nutrition Center examined the efficacy of dairy foods incorporated into a moderately energy restricted diet to reduce bone turnover and thereby minimize bone loss during weight loss. Individuals assigned to the low dairy (< 1 serving/d) weight loss diet had significantly greater bone resorption than those consuming adequate amounts (3-4 servings/d) of dairy-rich foods during weight loss. Additionally, the low dairy group had a significant decline in bone density at the hip and lower markers of bone formation. Overall the low dairy intake diet group demonstrated an imbalance between bone resorption and bone formation and decreased bone density at the hip, a high risk fracture site, compared to the group consuming adequate dairy (3-4 servings of dairy foods per day) as part of a weight loss program. These results suggest that a lack of dairy foods in a weight loss diet can have negative consequences for bone health.
2. Soybean peptide, lunasin, regulates gene expression through regulation of acetylation of histone proteins. There is growing evidence supporting the role of epigenetic modifications in cancer formation as the result of dysregulation of gene expression, especially in the early stages of carcinogenesis. Lunasin, a soy peptide, has been demonstrated to reduce tumor foci formation in vitro. Using immunocytochemistry, immunoprecipitation, and histone acetyltransferase assays, we showed that lunasin entered cells, bound to histone 4, and specifically inhibited acetylation of the lysine residue 8 (K8) of histone 4 (H4) while enhancing acetylation of H4K16 leading to lunasin-dependent upregulation of chemopreventive gene expression. These results show that a dietary peptide is capable of up-regulation of chemopreventive gene expression by specifc epigenetic modifications of the human genome. The research demonstrates a molecular mechanism that associates soy consumption with low cancer risk.
3. A novel method shows vitamin B12 is well-absorbed from eggs. Eggs are a potentially important source of vitamin B12 since there is 27% of the Recommended Dietary Allowance of 2.4 ug/day in the yolk of a single egg, and animal source foods are the only natural source of the vitamin, but there is limited information on how well the vitamin is absorbed from eggs. There are vitamin B12-binding proteins in both egg yolk and egg white and some past studies showed that these can substantially reduce the efficiency of absorption (bioavailability) of the vitamin in humans. Working with University of California collaborators who used a novel method of producing the vitamin labeled with the isotope 14C in bacteria, ARS researchers at the Western Human Nutrition Research Center, in Davis, CA, injected the labeled vitamin into hens to produce eggs that contained very low amounts of this radioactive B12. These eggs were fed to 10 human volunteers and the amount of 14C in their plasma, and excreted in feces and urine over a week, was measured by the very sensitive method of accelerator mass spectrometry at Lawrence Livermore National Laboratories. The vitamin was well absorbed, with about 50% absorbed from 1.5 ug and 20% from a 2.6 ug dose, showing that eggs are a good source of the vitamin. This research also provided new evidence for the degradation of unabsorbed vitamin B12 in the intestinal tract and its subsequent excretion as metabolites in urine, and on the marked reduction in efficiency of absorption of B12 across the usual range of intake.
Garrod, M.G., Allen, L.H., Haan, M.N., Green, R., Miller, J.W. 2010. Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older Hispanics. European Journal of Clinical Nutrition. 64, 503-509.