Grand Forks Human Nutrition Research Center

Obesity is traditionally viewed to be beneficial to bone health because of well-established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up-regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index ≥ 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health. The rates of obesity rates have doubled since 1980 and as of 2007, 33% of men and 35% of women in the US are obese. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year.Bone mass and strength decrease during adulthood, especially in women after menopause. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation and vice versa, those inhibiting osteoblastogenesis increased adipogenesis. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host⁻microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome.

DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B(12), vitamin B(6), methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adeno-sylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B(12), alcohol, and selenium may modify the response to inadequate dietary folate.

The essential trace element, selenium (Se), has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

A study was done to examine the effects of aluminum, magnesium, and boron on major mineral metabolism in postmenopausal women. This communication describes some of the effects of dietary boron on 12 women between the ages of 48 and 82 housed in a metabolic unit. A boron supplement of 3 mg/day markedly affected several indices of mineral metabolism of seven women consuming a low-magnesium diet and five women consuming a diet adequate in magnesium; the women had consumed a conventional diet supplying about 0.25 mg boron/day for 119 days. Boron supplementation markedly reduced the urinary excretion of calcium and magnesium; the depression seemed more marked when dietary magnesium was low. Boron supplementation depressed the urinary excretion of phosphorus by the low-magnesium, but not by the adequate-magnesium, women. Boron supplementation markedly elevated the serum concentrations of 17 beta-estradiol and testosterone; the elevation seemed more marked when dietary magnesium was low. Neither high dietary aluminum (1000 mg/day) nor an interaction between boron and aluminum affected the variables presented. The findings suggest that supplementation of a low-boron diet with an amount of boron commonly found in diets high in fruits and vegetables induces changes in postmenopausal women consistent with the prevention of calcium loss and bone demineralization.

Improving diet quality while simultaneously reducing environmental impact is a critical focus globally. Metrics linking diet quality and sustainability have typically focused on a limited suite of indicators, and have not included food waste. To address this important research gap, we examine the relationship between food waste, diet quality, nutrient waste, and multiple measures of sustainability: use of cropland, irrigation water, pesticides, and fertilizers. Data on food intake, food waste, and application rates of agricultural amendments were collected from diverse US government sources. Diet quality was assessed using the Healthy Eating Index-2015. A biophysical simulation model was used to estimate the amount of cropland associated with wasted food. This analysis finds that US consumers wasted 422g of food per person daily, with 30 million acres of cropland used to produce this food every year. This accounts for 30% of daily calories available for consumption, one-quarter of daily food (by weight) available for consumption, and 7% of annual cropland acreage. Higher quality diets were associated with greater amounts of food waste and greater amounts of wasted irrigation water and pesticides, but less cropland waste. This is largely due to fruits and vegetables, which are health-promoting and require small amounts of cropland, but require substantial amounts of agricultural inputs. These results suggest that simultaneous efforts to improve diet quality and reduce food waste are necessary. Increasing consumers' knowledge about how to prepare and store fruits and vegetables will be one of the practical solutions to reducing food waste.

Dietetic professionals urge Americans to increase fruit and vegetable intakes. The American Institute of Cancer Research estimates that if the only dietary change made was to increase the daily intake of fruits and vegetables to 5 servings per day, cancer rates could decline by as much as 20%. Among the reasons cited for this health benefit are that fruits and vegetables are excellent sources of fiber, vitamins, and minerals. They also contain nonnutritive components that may provide substantial health benefits beyond basic nutrition. Examples of the latter are the glucosinolate hydrolysis products, sulforaphane, and indole-3-carbinol. Epidemiological studies provide evidence that the consumption of cruciferous vegetables protects against cancer more effectively than the total intake of fruits and vegetables. This review describes the anticarcinogenic bioactivities of glucosinolate hydrolysis products, the mineral selenium derived from crucifers, and the mechanisms by which they protect against cancer. These mechanisms include altered estrogen metabolism, protection against reactive oxygen species, altered detoxification by induction of phase II enzymes, decreased carcinogen activation by inhibition of phase I enzymes, and slowed tumor growth and induction of apoptosis.

The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2X‐RDA), and 2.4 (3X‐RDA) g kg –1 d –1 for 31 d. A 10‐d weight‐maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9‐10) and ED (d 30‐31). Volunteers lost ( P &lt;0.05) 3.2 ± 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat‐free mass was lower ( P &lt;0.05) and the loss of fat mass was higher ( P &lt;0.05) in those receiving 2X‐RDA and 3X‐RDA compared to RDA. The anabolic muscle response to a protein‐rich meal during ED was not different ( P &gt;0.05) from WM for 2X‐RDA and 3X‐RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy × protein interaction, P &lt;0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat‐free mass during short‐term weight loss.—Pasiakos, S. M., Cao, J. J., Margolis, L. M., Sauter, E. R., Whigham, L. D., McClung, J. P., Rood, J. C., Carbone, J. W., Combs, G. F., Jr., Young, A. J. Effects of high‐protein diets on fat‐free mass and muscle protein synthesis following weight loss: a randomized controlled trial. FASEB J. 27, 3837–3847 (2013). www.fasebj.org

Abstract: Animal studies have shown that magnesium deficiency induces an inflammatory response that results in leukocyte and macrophage activation, release of inflammatory cytokines and acute-phase proteins, and excessive production of free radicals. Animal and in vitro studies indicate that the primary mechanism through which magnesium deficiency has this effect is through increasing cellular Ca 2+ , which is the signal that results in the priming of cells to give the inflammatory response. Primary pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-1; the messenger cytokine IL-6; cytokine responders E-selectin, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1; and acute-phase reactants C-reactive protein and fibrinogen have been determined to associate magnesium deficiency with chronic low-grade inflammation (inflammatory stress). When magnesium dietary intake, supplementation, and/or serum concentration suggest/s the presence of magnesium deficiency, it often is associated with low-grade inflammation and/or with pathological conditions for which inflammatory stress is considered a risk factor. When magnesium intake, supplementation, and/or serum concentration suggest/s an adequate status, magnesium generally has not been found to significantly affect markers of chronic low-grade inflammation or chronic disease. The consistency of these findings can be modified by other nutritional and metabolic factors that affect inflammatory and oxidative stress. In spite of this, findings to date provide convincing evidence that magnesium deficiency is a significant contributor to chronic low-grade inflammation that is a risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. Because magnesium deficiency commonly occurs in countries where foods rich in magnesium are not consumed in recommended amounts, magnesium should be considered an element of significant nutritional concern for health and well-being in these countries. Keywords: magnesium deficiency, magnesium adequacy, inflammatory stress, oxidative stress, chronic disease

Abstract The yield of wheat ( Triticum aestivum L. em. Thell) has greatly improved through breeding, but it is not known how this has affected seed micronutrient content. In the present study, the iron (Fe), zinc (Zn), copper (Cu), and selenium (Se) content of seed of 14 US hard red winter wheat varieties from production eras spanning more than a century was measured. The seed that was analyzed was obtained from a replicated field trial conducted at two locations in Kansas. The Fe, Zn, and Cu content was obtained by inductively coupled plasma emission spectroscopy (ICPES) and Se content was obtained by hydride‐generated atomic absorption spectrometry (HG‐AAS). Significant effects of location on micronutrient content of seed were observed. Similarly, depending on the micronutrient, significant differences in seed micronutrient content between varieties were detected at one or both locations. A significant negative regression of seed Zn content on both yield and variety release date was observed at both locations, while seed Fe content exhibited a significant negative regression on yield and variety release date at one location. Regression of seed Se content on variety release date was significant and negative at one location. These results suggest that genetic gains in the yield of US hard red winter wheat have tended to reduce seed Fe, Zn, and Se concentrations. However, the extent to which this effect manifests itself is influenced by environmental effects. Published in 2006 by John Wiley &amp; Sons, Ltd

About 60% of adults in the United States do not consume the estimated average requirement for magnesium, but widespread pathological conditions attributed to magnesium deficiency have not been reported. Nevertheless, low magnesium status has been associated with numerous pathological conditions characterized as having a chronic inflammatory stress component. In humans, deficient magnesium intakes are mostly marginal to moderate (approximately 50% to <100% of the recommended dietary allowance). Animal experiments indicate that signs of marginal-to-moderate magnesium deficiency can be compensated or exacerbated by other factors influencing inflammatory and oxidative stress; recent studies suggest a similar happening in humans. This suggestion may have significance in obesity, which is characterized as having a chronic low-grade inflammation component and an increased incidence of a low magnesium status. Marginal-to-moderate magnesium deficiency through exacerbating chronic inflammatory stress may be contributing significantly to the occurrence of chronic diseases such as atherosclerosis, hypertension, osteoporosis, diabetes mellitus, and cancer.

Many epidemiological and experimental studies have suggested that dietary fiber plays an important role in colon cancer prevention. These findings may relate to the ability of fiber to reduce the contact time of carcinogens within the intestinal lumen and to promote healthy gut microbiota, which modifies the host's metabolism in various ways. Elucidation of the mechanisms by which dietary fiber-dependent changes in gut microbiota enhance bile acid deconjugation, produce short chain fatty acids, and modulate inflammatory bioactive substances can lead to a better understanding of the beneficial role of dietary fiber. This article reviews the current knowledge concerning the mechanisms via which dietary fiber protects against colon cancer.

Evidence from numerous laboratories using a variety of experimental models, including humans, shows that boron is a bioactive beneficial element. Much evidence has come from studies that did not require nutritional or environmental stressors or fastidious methods in diet preparation or environmental control. The evidence includes deprivation studies showing that boron is necessary for some higher animals to complete the life cycle, and that realistic low boron intakes result in impaired bone health, brain function, and immune response. Thus, low boron intake is a relevant nutritional concern, which diets rich in fruits, vegetables, nuts, and pulses can prevent.

Definition of specific biochemical functions in higher animals (including humans) for the ultratrace elements boron, silicon, vanadium, nickel, and arsenic still has not been achieved although all of these elements have been described as being essential nutrients. Recently, many new findings from studies using molecular biology techniques, sophisticated equipment, unusual organisms, and newly defined enzymes have revealed possible sites of essential action for these five elements. Based on these findings and the response of animals and/or humans to low intakes of these elements, the following speculations have been presented: 1) Boron has a role that affects cell membrane characteristics and transmembrane signaling. 2) Silicon is necessary for the association between cells and one or more macromolecules such as osteonectin, which affects cartilage composition and ultimately cartilage calcification. 3) Vanadium reacts with hydrogen peroxide to form a pervanadate that is required to catalyze the oxidation of halide ions and/or stimulate the phosphorylation of receptor proteins. 4) Nickel is needed for the CO2-fixation to propionyl-CoA to form D-methylmalonyl-CoA. 5) Arsenic has an important role in the conversion of methionine to its metabolites taurine, labile methyl, and the polyamines. If any of these speculations are found to be true, the element involved will be firmly established as having a nutritional requirement because the body obviously cannot synthesize it. Based on animal findings, the dietary requirement is likely to be small; that is, expressed in micrograms per day.

PURPOSE OF REVIEW: To discuss recent research related to anticarcinogenic mechanisms of selenium action in light of the underlying chemical/biochemical functions of the selenium species, likely to be executors of those effects. RECENT FINDINGS: Recent studies in a variety of model systems have increased the understanding of the anticarcinogenic mechanisms of selenium compounds. These include effects on gene expression, DNA damage and repair, signaling pathways, regulation of cell cycle and apoptosis, metastasis and angiogenesis. These effects would appear to be related to the production of reactive oxygen species produced by the redox cycling, modification of protein-thiols and methionine mimicry. Three principle selenium metabolites appear to execute these effects: hydrogen selenide, methylselenol and selenomethionine. The fact that various selenium compounds can be metabolized to one or more of these species but differ in anticarcinogenic activity indicates competing pathways of their metabolic and chemical/biochemical disposition. Increasing knowledge of selenoprotein polymorphisms has shown that at least some are related to cancer risk and may affect carcinogenesis indirectly by influencing selenium metabolism. SUMMARY: The anticarcinogenic effects of selenium compounds constitute intermediate mechanisms with several underlying chemical/biochemical mechanisms such as redox cycling, alteration of protein-thiol redox status and methionine mimicry.

BACKGROUND: Our previous studies showed that transgenic mice that overexpress cardiac-specific metallothionein (MT) are highly resistant to diabetes-induced cardiomyopathy. Zinc is the major metal that binds to MT under physiological conditions and is a potent inducer of MT. The present study therefore explored whether zinc supplementation can protect against diabetic cardiomyopathy through cardiac MT induction. METHODS AND RESULTS: Diabetes was induced in mice (C57BL/6J strain) by a single injection of streptozotocin. Half were supplemented intraperitoneally with zinc sulfate (5 mg/kg) every other day for 3 months. After zinc supplementation, mice were maintained for 3 more months and then examined for cardiomyopathy by functional and morphological analysis. Significant increases in cardiac morphological impairment, fibrosis, and dysfunction were observed in diabetic mice but not in diabetic mice supplemented with zinc. Zinc supplementation also induced a significant increase in cardiac MT expression. The role of MT in cardiac protection by zinc supplementation was examined in cultured cardiac cells that were directly exposed to high levels of glucose (HG) and free fatty acid (FFA) (palmitate), treatment that mimics diabetic conditions. Cell survival rate was significantly decreased for cells exposed to HG/FFA but did not change for cells exposed to HG/FFA and pretreated with zinc or low-dose cadmium, each of which induces significant MT synthesis. When MT expression was silenced with the use of MT small-interfering RNA, the preventive effect of pretreatment with zinc or low-dose cadmium was abolished. CONCLUSIONS: These results suggest that the prevention of diabetic cardiomyopathy by zinc supplementation is predominantly mediated by an increase in cardiac MT.

ABSTRACT T hermal and other physicochemical properties of starch from 42 potato genotypes were studied to find those with unique properties for food use, and to analyze relationships between thermal and other physicochemical properties. Onset and peak transition temperatures and gelatinization enthalpy intercorrelated. Transition temperatures intercorrelated with pasting temperature using a Brabender Visco‐amylograph. Gelatinization entbalpy correlated with Brabender pasting temperature and peak paste viscosity, and onset temperature correlated with phosphorus content. Genotype E55–3.5 with highest onset and peak transition temperatures also had highest phosphorus and peak Brabender viscosity. DSC might be useful for rapidly screening samples of &lt;1g starch for such. Potato starch DSC characteristics did not correlate with amylose, intrinsic viscosity, or water‐binding. For 10 genotypes from successive years, correlations were observed for pasting temperature (r = 0.83), phosphorus content (r = 0.80), and stability ratio (r = 0.66). Direct comparison between samples from consecutive years showed good reproducibility for amylose, but not for phosphorus or pasting.

Mathematical equations using tetrapolar bioelectrical resistive (R) and reactive (Xc) impedance measures were developed and crossvalidated to predict total body water (TBW) and corrected bromide space (CBS) in two independent samples (n = 110). Height2 per low R was the best predictor of TBW (R = 0.96) and CBS (R = 0.92). When the influence of TBW was removed from CBS and dependent variables, height2 per low Xc was the best predictor (R = 0.50) of CBS. Double crossvalidation of each sample showed that observed and predicted TBW (R = 0.978 and 9.986) and CBS (0.937 and 0.907) were significantly related (p less than 0.001), and there was no difference (p greater than 0.05) between the values. The lines representing the relationships between observed and predicted values had regression coefficients not different than the line of identity. Data from both samples were combined to give a representative multiple regression equation to predict TBW and CBS. This study establishes the validity of the tetrapolar bioelectrical impedance method to assess body fluid volumes in humans.

Chromium (Cr) is an essential mineral element that has received considerable public attention. The suggestion that Cr intake is generally low has generated interest regarding the purported beneficial effects of Cr supplementation on biological function and health of animals and humans. This review briefly describes key aspects of Cr nutritional status and evaluates the effects of Cr supplementation on various components of biological function, body composition, and health. A novel biological role of Cr in regulation of insulin function is described. Although promising results of Cr supplementation are presented, the considerable challenge of developing methods for routine assessment of Cr nutriture in humans remains.

Selenium is an essential trace element for humans and animals, and selenium deficiency is associated with several disease conditions such as immune impairment. In addition, selenium intakes that are greater than the recommended daily allowance (RDA) appear to protect against certain types of cancers. In humans and animals, cell proliferation and death must be regulated to maintain tissue homeostasis, and it has been well documented that numerous human diseases are directly related to the control of cell cycle progression and apoptosis. Thus, the elucidation of the mechanisms by which selenium regulates the cell cycle and apoptosis can lead to a better understanding of the nature of selenium's essentiality and its role in disease prevention. This article reviews the status of knowledge concerning the effect of selenium on cell cycle and apoptosis.