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1.  High Prevalence of Vitamin D Insufficiency in Black and White Pregnant Women Residing in the Northern United States and Their Neonates1 
The Journal of nutrition  2007;137(2):447-452.
In utero or early-life vitamin D deficiency is associated with skeletal problems, type 1 diabetes, and schizophrenia, but the prevalence of vitamin D deficiency in U.S. pregnant women is unexplored. We sought to assess vitamin D status of pregnant women and their neonates residing in Pittsburgh by race and season. Serum 25-hydroxyvitamin D (25(OH)D) was measured at 4–21 wk gestation and predelivery in 200 white and 200 black pregnant women and in cord blood of their neonates. Over 90% of women used prenatal vitamins. Women and neonates were classified as vitamin D deficient [25(OH)D <37.5 nmol/L], insufficient [25(OH)D 37.5–80 nmol/L], or sufficient [25(OH)D >80 nmol/L]. At delivery, vitamin D deficiency and insufficiency occurred in 29.2% and 54.1% of black women and 45.6% and 46.8% black neonates, respectively. Five percent and 42.1% of white women and 9.7% and 56.4% of white neonates were vitamin D deficient and insufficient, respectively. Results were similar at <22 wk gestation. After adjustment for prepregnancy BMI and periconceptional multivitamin use, black women had a smaller mean increase in maternal 25(OH)D compared with white women from winter to summer (16.0 ± 3.3 nmol/L vs. 23.2 ± 3.7 nmol/L) and from spring to summer (13.2 ± 3.0 nmol/L vs. 27.6 ± 4.7 nmol/L) (P < 0.01). These results suggest that black and white pregnant women and neonates residing in the northern US are at high risk of vitamin D insufficiency, even when mothers are compliant with prenatal vitamins. Higher-dose supplementation is needed to improve maternal and neonatal vitamin D nutriture.
PMCID: PMC4288960  PMID: 17237325
2.  Dietary Calcium is Associated with Body Mass Index and Body Fat in American Indians 
The Journal of nutrition  2007;137(8):1955-1960.
American Indians have a high prevalence of obesity. Evidence exists to support a relationship between increased dietary calcium intake and lower body weight. This study was conducted to investigate the association between dietary calcium intake, BMI, and percentage of body fat (PBF) in American Indians (ages 47–79 y) in the Strong Heart Study (SHS) (2nd exam: 1992–1995). SHS data were compared with data for the general U.S. adult population from the National Health and Nutrition Examination Survey (NHANES III) (1988–1994). BMI was calculated as weight (kg)/height (m2). PBF was estimated by bioelectrical impedance, using an equation based on total body water. The clinical examination included measures of blood chemistry. Dietary data were collected using a 24-h dietary recall. Calcium intake was significantly lower among SHS participants than among age-matched NHANES III participants. Mean calcium intake in the SHS was 680 mg/d (range: 103 – 4574 mg/d) for men and 610 mg/d (range: 71 – 4093 mg/d) for women (P < 0.001). After adjustment for potential confounders, BMI and PBF were lower by 0.80 kg/m2 (95% CI: −1.53 to −0.08, P = 0.046) and 1.28% (95% CI: −2.10 to −0.47, P = 0.011) in SHS participants with higher (≥ 873 mg/d in the 5th quintile) versus lower calcium intake (< 313 mg/d in the 1st quintile). No relation between calcium intake and BMI or PBF was observed in NHANES III participants. Our data may be used to develop nutritional interventions aimed at weight control in culturally appropriate clinical trials.
PMCID: PMC4182955  PMID: 17634270
Dietary calcium; BMI; Body fat; American Indians
3.  Zinc Deficiency Alters DNA Damage Response Genes in Normal Human Prostate Epithelial Cells123 
The Journal of nutrition  2008;138(4):667-673.
Zinc is an essential trace element for human health and is a critical component of many proteins and transcription factors involved in DNA damage response and repair. The prostate is known to accumulate high levels of zinc, but levels are markedly decreased with cancer development. We hypothesized that zinc plays a critical role in maintaining DNA integrity in the prostate and zinc deficiency would lead to increased DNA damage and altered DNA damage response mechanisms. To test this hypothesis, the goal of this study was to determine the effects of zinc deficiency on DNA damage and DNA repair mechanisms by examining changes in global gene expression and transcription factor binding abilities in normal prostate epithelial cells (PrEC). Increased single-strand DNA breaks (Comet assay) were observed in PrEC grown in zinc-deficient media compared with cells grown in zinc-adequate media for 7 d. Using Affymetrix HG-U133A gene chips, differential expression of genes involved in cell cycle, apoptosis, transcription, and DNA damage response and repair were identified with low cellular zinc. Among genes involved in DNA damage response and repair were identified with low cellular zinc. Among genes involved in DNA damage response and repair, tumor protein p73,,tumor protein p73,MRE11 meiotic recombination 11 homolog A,X-ray repair complementing defective repair in Chinese hamster cells 4, and breast cancer 2, early onset were down-regulated and TP53 was up-regulated. Additionally, western blotting showed increased nuclear p53 protein expression with zinc deficiency. Despite increased p53 gene and nuclear protein expression, there was no significant change in p53 binding activity. Zinc deficiency also induced an increase in binding activity of transcription factors involved in regulating cell proliferation and apoptosis. Thus, zinc deficiency may compromise DNA integrity in the prostate by impairing the function of zinc-containing proteins.
PMCID: PMC4152237  PMID: 18356318
4.  Fatty Acid Binding Proteins—The Evolutionary Crossroads of Inflammatory and Metabolic Responses1 
The Journal of nutrition  2004;134(9):2464S-2468S.
Fatty acid binding proteins (FABPs) are members of a highly conserved family of proteins with the task of protecting a cell’s delicate lipid balance. Yet they fail when faced with metabolic or inflammatory stress, turning the cytosol into an inhospitable environment with less than ideal outcomes. This review will focus on how FABPs direct lipid traffic and simultaneously control inflammatory and metabolic pathways under the pressures of the Metabolic Syndrome.
PMCID: PMC4027055  PMID: 15333743
fatty acid binding protein (FABP); Metabolic Syndrome; inflammation; obesity; insulin resistance
5.  Bone, Body Weight, and Weight Reduction: What Are the Concerns?1,2 
The Journal of nutrition  2006;136(6):1453-1456.
Of the U.S. population, 65% is either overweight or obese, and weight loss is recommended to reduce co-morbid conditions. However, bone mobilization and loss may also occur with weight loss. The risk for bone loss depends on initial body weight, age, gender, physical activity, and conditions of dieting such as the extent of energy restriction and specific levels of nutrient intake. Older populations are more prone to bone loss with weight loss; in women, this is due at least in part to a reduced dietary Ca intake and/or efficiency of absorption. Potential hormonal mechanisms regulating bone loss during weight loss are discussed, including decreases in estrogen, leptin, glucagon-like peptide-2, growth hormone, and insulin-like growth factor-1, or an increase in cortisol. In contrast, the rise in adiponectin and ghrelin with weight reduction should not be detrimental to bone. Combining energy restriction with exercise does not necessarily prevent bone loss, but may attenuate loss as was shown with additional Ca intake or osteoporosis medications. Future controlled weight loss trials should be designed to further address mechanisms influencing the density and quality of bone sites vulnerable to fracture, in the prevention of osteoporosis.
PMCID: PMC4016235  PMID: 16702302
bone; calcium; diet; osteoporosis; weight loss
6.  Energy Restriction Reduces Fractional Calcium Absorption in Mature Obese and Lean Rats1,2 
The Journal of nutrition  2002;132(9):2660-2666.
Weight loss is associated with bone loss and the risk may be greater in lean than heavier individuals, but the mechanisms involved remain unclear. We hypothesized that energy restriction (EnR) would decrease true fractional Ca absorption (TFCA) and be mediated by Ca-regulating hormones, but differently in obese and lean rats. Rats were fed a high fat (47% energy) or low fat (16% energy) diet for 4 mo. At 6 mo of age, the resulting lean [284 ± 28g (mean ± sd, n = 18)] and obese (319 ± 34g, n = 20) groups (P < 0.005) were divided into controls (CTL, ad libitum) and energy-restricted (40% restriction) groups. At baseline, bone resorption (urinary crosslinks) was higher and bone formation (serum osteocalcin) was lower in obese than in lean rats, whereas Ca balance components and Ca-regulating hormones did not differ. EnR for 10 wk reduced body weight by 25 ± 7% compared with a 6 ± 6% gain in CTL rats (P < 0.001). For both lean and obese rats, TFCA (5-d measurement, 45Ca radioisotope) decreased from 30 ± 9% to 24 ± 9% with EnR, compared with 25 ± 10% to 29 ± 11% in controls (P < 0.05). Weight loss was directly correlated with the decrease in TFCA (r = 0.34, P < 0.05). Uterine weights indicated a reduced estrogenic activity in energy-restricted rats (P < 0.0001). In lean, but not obese rats, serum estradiol (E2) correlated with weight loss (r = 0.52, P < 0.05), and tended to correlate with the decrease in TFCA (r = 0.48, P = 0.06). At the end of the study, serum 25-hydroxyvitamin-D was lower and urinary Ca was higher in lean than obese energy-restricted rats. Distinct endocrine profiles during weight loss in obese and lean rats suggest that the susceptibility of bone and Ca metabolism to EnR could differ depending on initial body weight.
PMCID: PMC4010555  PMID: 12221226
absorption; calcium; estrogen; rats; weight loss
7.  Energy Restriction Reduces Bone Density and Biomechanical Properties in Aged Female Rats1,2 
The Journal of nutrition  2001;131(9):2382-2387.
Bone mineral density (BMD) is highly correlated with body weight, and weight loss is associated with reduced BMD. Whether such losses of BMD increase skeletal fragility is unclear. We examined the effect of 9 wk of energy restriction (ER) on bone density, mineral and matrix protein composition and biomechanical properties in mature (20 wk old, n = 12) and aged (48 wk old, n = 16) female rats. Energy-restricted rats were fed 40% less energy than controls that consumed food ad libitum. Bone content of mineral (ash and calcium content) and matrix proteins (hydroxyproline, pyridinium crosslinks and proteoglycans), serum hormones, site-specific bone density and biomechanical properties (peak load, peak torque, shear stiffness and bending stiffness) were measured at the conclusion of the study. In both age groups, ER reduced body weight by 15 ± 10% (P < 0.001) and dramatically decreased femoral bone density by 32–35% (P < 0.01) compared with controls. Energy restriction resulted in a small reduction in tibia and humerus density, as well as biomechanical properties in the aged but not mature rats (P < 0.05). Reduced serum levels of insulin and estradiol due to ER in aged rats (P < 0.05) may play a role in altering bone quality. These data show that although weight loss due to ER is detrimental to some bone parameters in mature rats, only aged rats show consistent reductions in bone density and biomechanical properties.
PMCID: PMC4008883  PMID: 11533283
bone; biomechanical; energy restriction; diet; rats
8.  Estrogen Prevents the Reduction in Fractional Calcium Absorption Due to Energy Restriction in Mature Rats1 
The Journal of nutrition  2004;134(8):1929-1934.
Weight reduction is a risk factor for bone loss. We previously showed that energy restriction is associated with a decrease in calcium (Ca) absorption and decreased estrogenic activity (EA). We hypothesized that this hypoestrogenic status may be the cause of the decrease in Ca absorption and that estrogen replacement during energy restriction would prevent it. Six-month-old rats were ovariectomized and implanted subcutaneously with 17β-estradiol (E2) pellets to maintain levels within the physiological range. After 3 wk, rats ate ad libitum [control (CTL) group, n = 12] or were 40% energy restricted (EnR group, n = 12) for 10 wk. At the end of this study, rats were divided into 2 groups according to their uterine weight: those with higher EA and those with lower EA. Whereas CTL rats gained ~46% weight from baseline, EnR rats maintained their weight throughout the study. Energy restriction was associated with lower Ca absorption (5-d measurement, 45Ca radioisotope) and Ca balance in lower EA but not higher EA rats. Similarly, Ca absorption was correlated with both serum E2 (r = 0.68, P < 0.05) and body weight (r = 0.72, P < 0.05) in rats with lower EA but not in those with higher EA. Finally, 24-h corticosterone excretion was higher in EnR than in CTL rats, a response that was blunted in the higher EA rats. Our findings suggest that decreases in estrogen and hyperadrenocorticism with energy restriction play an important role in the regulation of Ca absorption and balance.
PMCID: PMC4006999  PMID: 15284378
absorption; calcium; estrogen; corticosterone; weight loss
9.  Low Adherence to Dietary Recommendations for Saturated Fat, Fiber, and Sodium Found Among American Indians and Other U.S. Adults with Diabetes* 
The Journal of nutrition  2008;138(9):1699-1704.
The objective of this article was to evaluate how well American Indians with diabetes met dietary recommendations and to compare adherence to dietary recommendations with those of U.S. adults with diabetes in the National Health and Nutrition Examination Survey (NHANES). Dietary intake in both studies was assessed using a 24-h recall questionnaire. Dietary intakes were evaluated against American Diabetes Association (ADA) dietary recommendations. The analysis sample consisted of 1,008 participants from SHS examined from 1997–1999 and 373 participants from NHANES examined from 1999–2000, all with diabetes. In both samples, intake of protein, polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), and carbohydrates met the 1997 ADA dietary recommendations. However, intakes of saturated fatty acid (SFA) as well as sodium were higher and dietary fiber intake was lower than recommended. In the SHS and NHANES, only 4.6% and 8.5% of persons with diabetes met recommendations for both SFA and fiber (p = 0.02), respectively. However, only 8.3% of the NHANES sample met the 2006 recommendations for SFA and fiber, and none of the SHS sample met those recommendations. This cross-sectional study shows low adherence to ADA dietary recommendations for saturated fat, fiber, and sodium by American Indians with diabetes and by the broader U.S. population of adults with diabetes, and shows that in American Indians with diabetes programs to decrease SFA and increase fiber intakes are warranted.
PMCID: PMC3997118  PMID: 18716172
10.  Retinoic Acid Therapy Attenuates the Severity of Tuberculosis While Altering Lymphocyte and Macrophage Numbers and Cytokine Expression in Rats Infected with Mycobacterium tuberculosis1,2,3 
The Journal of nutrition  2007;137(12):2696-2700.
Because retinoic acid (RA) exerts a stimulatory effect on macrophages and tubercle bacilli target alveolar macrophages, the therapeutic potential of RA was examined in rats with tuberculosis. In the main study, 15 rats were randomized to treatment with oil (control) or RA,100 µg/100 g body weight per dose, given 3 times weekly for 3 and 5 wk after infection with Mycobacterium tuberculosis strain H37Rv. There was a significant difference in the severity of tuberculosis histopathology between control and RA-treated rats, and oral administration of RA decreased the number of colony-forming units (CFU) in both lung and spleen at 3 and 5 wk after H37Rv infection (P < 0.005). CD4-positive and CD8-positive T cells, natural killer cells, and CD163-positive macrophages increased (P < 0.05) in the infected lung tissues of RA-treated rats. Expression of IFNγ and inducible nitric oxide synthetase messenger RNA (mRNA) was higher in the infected lung tissues of RA-treated rats than in control rats. Alveolar macrophages from rats treated in vivo with RA and infected in vitro with M. tuberculosis showed significantly higher expression of TNFα and IL-1β mRNA than macrophages in control rats. To our knowledge, this is the first reported study to demonstrate that orally administered RA significantly inhibits the in vivo growth of M. tuberculosis and the development of tuberculosis.
PMCID: PMC3898622  PMID: 18029486
11.  Nutrient Ingestion, Protein Intake, and Sex, but Not Age, Affect the Albumin Synthesis Rate in Humans123 
The Journal of nutrition  2007;137(7):1734-1740.
The aim of this study was to assess the effects of nutrient ingestion, dietary protein intake, age, and sex on the fractional synthesis rate (FSR) of albumin. Thirty-six healthy free-living individuals (8 females and 10 males aged 21–43 y and 9 females and 9 males aged 63–79 y) completed three 18-d periods of controlled feeding with protein intakes of 125% (P125, 1.00 g protein · kg−1 · d−1), 94% (P94, 0.75 g protein · kg−1 · d−1), and 63% (P63, 0.50 g protein · kg−1 · d−1) of the recommended dietary allowance. On d 12 of each trial, postabsorptive (PA) serum albumin concentration was determined and PA and postprandial (PP) albumin FSR were estimated from the rate of L-[1-13C] leucine incorporation into plasma albumin during an 8-h infusion. There were no age-related differences in PA and PP albumin FSR. Albumin FSR was higher PP than PA (P < 0.0001), and the increase in albumin FSR from PA to PP was smaller as dietary protein intake decreased from P125 to P94 and P63 (P < 0.05). Independent of protein intake, males had a higher albumin FSR (P < 0.05) and a greater increase in albumin FSR with feeding (P < 0.05). There was no age or dietary protein effect on serum albumin concentrations, but males had higher albumin concentrations than females (P < 0.0001). These results show that older persons are responsive to nutrient ingestion and dietary protein-related changes in albumin FSR. The greater albumin synthesis rate in males might contribute to a higher albumin concentration set point.
PMCID: PMC3885871  PMID: 17585023
12.  Lung Retinyl Ester Is Low in Young Adult Rats Fed a Vitamin A–Deficient Diet after Weaning, despite Neonatal Vitamin A Supplementation and Maintenance of Normal Plasma Retinol1,2 
The Journal of nutrition  2007;137(10):2213-2218.
Although it is understood that plasma retinol concentration is not proportional to the concentration of vitamin A stored in liver, plasma retinol still is often used as an indicator of vitamin A status. An aim of vitamin A supplementation strategies is to maintain plasma retinol concentration in a range considered adequate, generally >1.05 µmol/L in humans, with some adjustment for age. In the present study in rats, we addressed the following question: Does lung vitamin A increase postnatally, as is observed in rats fed a vitamin A–adequate diet, if plasma retinol is maintained at ~1 µmol/L by supplementation at neonatal age, but the weaning diet is deficient in vitamin A? We treated rats on postnatal d 6, 7, and 8 with placebo (oil), vitamin A, retinoic acid (RA), and a nutrient-metabolite combination of vitamin A and RA, VARA, after which tissues were analyzed on d 9. Other rats treated identically as neonates were fed a vitamin A–deficient diet from 3–9 wk of age, and in parallel, another group of rats was fed a vitamin A–adequate diet. Although supplementation with vitamin A or VARA elevated liver and lung retinyl esters (RE) on d 9 (P < 0.0001), and prevented the fall in plasma retinol to <1 µmol/L by 9 wk of age, when the diet was vitamin A–deficient, lung RE fell to 28% of the concentration present in the lungs of rats fed the vitamin A–adequate diet (P < 0.0001). We infer that the lungs depend, at least in part, on the uptake of dietary vitamin A, probably from chylomicrons, to develop RE stores in the postweaning growth period.
PMCID: PMC3843128  PMID: 17885000
13.  The Components of VARA, a Nutrient-Metabolite Combination of Vitamin A and Retinoic Acid, Act Efficiently Together and Separately to Increase Retinyl Esters in the Lungs of Neonatal Rats1 
The Journal of nutrition  2006;136(11):2803-2807.
Retinoic acid (RA), produced from vitamin A (VA, retinol), is required for normal lung development and postnatal lung maturation. The concentration of retinyl ester (RE), the major storage form of retinol, decreases in the lungs in the perinatal period. Previously, we tested VARA, a nutrient-metabolite combination of VA and RA (10:1 molar ratio), on lung RE formation in postnatal rats and showed that the components of VARA acted synergistically to increase lung RE, as compared with the effects of equal amounts of VA and RA given alone. In this study, we first determined the equivalency of orally administered VARA in comparison to a standard oral supplement of VA, with respect to lung and liver RE storage. In a dose-dilution study, VARA was 4 times as effective as the standard dose of VA (VARA-25% did not differ from VA-100%). The synergistic effect of VARA was selective for the lungs, compared with the liver, in which VA and VARA had equal effects. Secondly, we tested whether the 2 components of VARA must be coadministered to exert their synergistic effect on lung RE content. RA and VA and were administered separately and together as VARA. Although RA alone had no effect on lung RE in this 24-h experiment, RA synergized with VA administered either 12 h before RA or 12 h after RA, as well as when coadministered as VARA. We infer that VA and RA are both limiting for lung RE formation in neonates. Given the importance of bioactive retinoids in cell differentiation and lung development, assuring an adequate lung RE content postnatally could be of benefit for lung maturation.
PMCID: PMC3843131  PMID: 17056804
14.  Neonatal-Age Treatment with Vitamin A Delays Postweaning Vitamin A Deficiency and Increases the Antibody Response to T-cell Dependent Antigens in Young Adult Rats Fed a Vitamin A-Deficient Diet1,2 
The Journal of nutrition  2007;137(5):1229-1235.
Vitamin A supplementation for infants and young children is recommended by WHO/UNICEF for countries with a high prevalence of vitamin A deficiency, and vitamin A is often administered at immunization contacts. Using a rat model, we tested whether supplementation with vitamin A or other retinoids at the time of neonatal immunization has prospective benefit in terms of preventing postweaning vitamin A deficiency and promoting antibody responses to T-cell dependent (TD) antigens administered at the neonatal stage and at the young adult stage. Rats were treated orally on postnatal d 6–8 with oil (placebo control), vitamin A, retinoic acid, or a combination of both (VARA) (n ≥ 12/group), and immunized with tetanus toxoid (TT) on d 7. The primary anti-TT response was measured on d 21, after which weanling rats were fed the vitamin A-deficient diet until ~ 10 wk. At 8 wk, rats were immunized again with TT to determine the recall response, and with a novel TD antigen, keyhole limpet hemocyanin (KLH), to assess the adult primary response. None of the supplements affected the plasma titer of anti-TT immunoglobulinG (IgG) on d 21 (P = 0.25). However, neonatal-age supplementation with vitamin A or VARA at the young adult stage resulted in: >5 times higher anti-TT IgG recall response (P < 0.01); 5- and 9-times higher anti-KLH primary IgM and IgG responses, respectively (P < 0.05), and plasma retinol in the normal range (~1.0 µmol/L vs. ~0.35 µmol/L in retinoic acid-treated and control groups, P < 0.0001). We conclude that early-life supplementation with vitamin A or VARA can prospectively benefit the primary and recall antibody responses to TD antigens administered at the young adult stage, which may involve the maintenance of normal plasma retinol levels.
PMCID: PMC3843133  PMID: 17449586
15.  Chronic Vitamin A Status and Acute Repletion with Retinyl Palmitate Are Determinants of the Distribution and Catabolism of all-trans-Retinoic Acid in Rats1 
The Journal of nutrition  2007;137(1):63-70.
The relation between vitamin A (VA) nutritional status and the metabolism of all-trans-retinoic acid (RA) is not well understood. In this study, we determined the tissue distribution and metabolism of a test dose of [3H]-RA in rats with graded, diet-dependent, differences in VA status. The design included 3 groups, designated VA-deficient, VA-marginal, and VA-adequate, with liver total retinol concentrations of 9.7, 35.7 and 359 nmol/g, respectively, (P < 0.05), and an additional group of VA-deficient rats treated with a single oral dose of retinyl palmitate (RP) 20 h before the injection of [3H]-RA. Plasma, liver, lung, and small intestines, collected 30 min after [3H]-RA, were analyzed for total3H, unmetabolized [3H]-RA, polar organic-phase metabolites of [3H]-RA, and aqueous phase [3H]-labeled metabolites. In all groups, [3H]-RA was rapidly removed from plasma and concentrated in the liver. VA deficiency did not prevent the oxidative metabolism of RA. Nevertheless, the quantity of [3H]-RA metabolites in plasma and the ratio of total [3H]-polar metabolites to unmetabolized [3H]-RA in liver varied directly with VA status (VA-adequate > VA-marginal > VA-deficient, P < 0.05). Moreover, supplementation of VA-deficient rats with RP reduced the metabolism of [3H]-RA, similar to that in VA-adequate or VA-marginal rats. Liver retinol concentration, considered a proxy for VA status, was correlated (P < 0.05) with [3H]-RA metabolites in liver (R2 = 0.54), plasma (R2 = 0.44), lung (R2 =0.40), intestine (R2 =0.62), and all combined (R2 =0.655). Overall, the results demonstrate close linkage between dietary VA intake, hepatic storage of VA, and the degradation of RA and suggest that measuring plasma retinoid metabolites after a dose of RA may provide insight into the metabolism of this bioactive retinoid by visceral organs.
PMCID: PMC3843135  PMID: 17182802
16.  C-Reactive Protein and Interleukin-6 Are Decreased in Transgenic Sickle Cell Mice Fed a High Protein Diet1,2 
The Journal of nutrition  2008;138(6):1148-1152.
Sickle cell disease is associated with hypermetabolism and a consequent shortage of substrates for normal growth and healthy immune response. The protein:energy ratio is a major determinant of dietary adequacy; the requirement for optimal growth of control mice is 20% of energy from dietary protein. This study investigated the efficacy of increased dietary protein for improving weight gain and reducing inflammation in the Berkeley sickle cell mouse model (S). The study examined the effect of diet on weight gain and circulating levels of 2 inflammatory proteins, C-reactive protein (CRP), and cytokine interleukin-6 (IL-6). Male C57BL/6 (C) control (n = 8) and S mice (n = 8) were randomized at weaning to 40 d of isoenergetic diets containing 20% (normal) and 35% (high) of energy from protein (C20, C35, S20, S35), replacing dextrin. Rate of weight gain was calculated and plasma CRP and IL-6 concentrations determined by ELISA. Liver mRNA expression of these proteins was measured by real-time PCR and L-arginase by colorimetric assay. S35 mice tended to gain weight more rapidly than S20 mice (P = 0.06) and more rapidly than C35 mice (P < 0.01). Circulating CRP and IL-6 levels were also lower in S35 mice than in S20 mice (P < 0.05), as was liver CRP mRNA expression (P < 0.01). These results demonstrate that introducing a high protein diet at weaning attenuates the steady-state inflammation in this S mouse model. Dietary L-arginine availability was investigated as a possible mechanism for increased nitric oxide production and consequent reduced inflammation.
PMCID: PMC3755955  PMID: 18492848
17.  Prebiotic Fiber Increases Hepatic Acetyl CoA Carboxylase Phosphorylation and Suppresses Glucose-Dependent Insulinotropic Polypeptide Secretion More Effectively When Used with Metformin in Obese Rats1,2 
The Journal of nutrition  2012;142(2):213-220.
Independently, metformin (MET) and the prebiotic, oligofructose (OFS), have been shown to increase glucagon-like peptide (GLP-1) secretion. Our objective was to determine whether using OFS as an adjunct with MET augments GLP-1 secretion in obese rats. Male, diet-induced obese Sprague Dawley rats were randomized to: 1) high-fat/-sucrose diet [HFHS; control (C); 20% fat, 50% sucrose wt:wt]; 2) HFHS+10% OFS (OFS); 3) HFHS + MET [300 mg/kg/d (MET)]; 4) HFHS+10% OFS+MET (OFS +MET). Body composition, glycemia, satiety hormones, and mechanisms related to dipeptidyl peptidase 4 (DPP4) activity in plasma, hepatic AMP-activated protein kinase (AMPK; Western blots), and gut microbiota (qPCR) were examined. Direct effects of MET and SCFA were examined in human enteroendocrine cells. The interaction between OFS and MET affected fat mass, hepatic TG, secretion of glucose-dependent insulinotropic polypeptide (GIP) and leptin, and AMPKα2 mRNA and phosphorylated acetyl CoA carboxylase (pACC) levels (P < 0.05). Combined, OFS and MET reduced GIP secretion to a greater extent than either treatment alone (P < 0.05). The hepatic pACC level was increased by OFS+MET by at least 50% above all other treatments, which did not differ from each other (P < 0.05). OFS decreased plasma DPP4 activity (P < 0.001). Cecal Bifidobacteria (P < 0.001) were markedly increased and C. leptum decreased (P < 0.001) with OFS consumption. In human enteroendocrine cells, the interaction between MET and SCFA affected GLP-1 secretion (P < 0.04) but was not associated with higher GLP-1 than the highest individual doses. In conclusion, the combined actions of OFS and MET were associated with important interaction effects that have the potential to improve metabolic outcomes associated with obesity.
PMCID: PMC3742459  PMID: 22223580 CAMSID: cams3220
18.  Sitagliptin Reduces Hyperglycemia and Increases Satiety Hormone Secretion More Effectively When Used with a Novel Polysaccharide in Obese Zucker Rats123 
The Journal of nutrition  2012;142(10):1812-1820.
The novel polysaccharide (NPS) PolyGlycopleX (PGX) has been shown to reduce glycemia. Pharmacological treatment with sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, also reduces glycemia by increasing glucagon-like peptide-1 (GLP-1). Our objective was to determine if using NPS in combination with sitagliptin reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than either treatment alone. Male ZDF rats were randomized to: 1) cellulose/vehicle [control (C)]; 2) NPS (5% wt:wt)/vehicle (NPS); 3) cellulose/sitagliptin [10 mg/(kg · d) (S)]; or 4) NPS (5%) + S [10 mg/(kg · d) (NPS+S)]. Glucose tolerance, adiposity, satiety hormones, and mechanisms related to DPP4 activity and hepatic and pancreatic histology were examined. A clinically relevant reduction in hyperglycemia occurred in the rats treated with NPS+S (P = 0.001) compared with NPS and S alone. Blood glucose, measured weekly in fed and feed-deprived rats and during an oral glucose tolerance test, was lower in the NPS+S group compared with all other groups (all P = 0.001). At wk 6, glycated hemoglobin was lower in the NPS+S group than in the C and S (P = 0.001) and NPS (P = 0.06) groups. PGX (P = 0.001) and S (P = 0.014) contributed to increased lean mass. Active GLP-1 was increased by S (P = 0.001) and GIP was increased by NPS (P = 0.001). Plasma DPP4 activity was lower in the NPS+S and S groups than in the NPS and C groups (P = 0.007). Insulin secretion and β-cell mass was increased with NPS (P < 0.05). NPS alone reduced LDL cholesterol and hepatic steatosis (P < 0.01). Independently, NPS and S improve several metabolic outcomes in ZDF rats, but combined, their ability to markedly reduce glycemia suggests they may be a promising dietary/pharmacological co-therapy for type 2 diabetes management.
PMCID: PMC3718709  PMID: 22915295 CAMSID: cams3204
19.  Carboxyl Ester Lipase from Either Mother’s Milk or the Pancreas Is Required for Efficient Dietary Triglyceride Digestion in Suckling Mice1,2 
The Journal of nutrition  2008;138(5):927-930.
Because dietary fats provide an important source of energy in the newborn, the efficient digestion of dietary fats is critical to their well-being. Despite the importance of dietary fat digestion, newborns have a deficiency of pancreatic triglyceride lipase, the predominant digestive lipase in adults. The efficient dietary fat digestion in newborns suggests that other lipases must compensate for the lack of pancreatic triglyceride lipase. In this study, we test the hypothesis that breast milk, pancreatic carboxyl ester lipase (CEL), or both contribute to dietary fat digestion in the newborn. To test this hypothesis, we determined the amount and composition of fecal fat in wild-type and CEL-deficient newborns nursed by either wild-type or CEL-deficient dams. We tested all genetic permutations of the nursing pairs. An interaction between the genotype of the dam and of the pup determined the amount of fecal fat (P < 0.001). Fecal fat was highest in CEL-deficient pups nursed by CEL-deficient dams. Furthermore, only the feces from the CEL-deficient pups nursed by CEL-deficient dams contained undigested lipids. Even with increased fecal fats, the CEL-deficient pups had normal weight gain. Our results demonstrate that CEL contributes significantly to dietary triglyceride digestion whether it originates from mother’s milk or pancreatic secretions. However, only the absence of both mother’s milk and pancreatic CEL produces fat maldigestion. The absence of a single CEL source makes no difference in the efficiency of dietary fat absorption.
PMCID: PMC3687517  PMID: 18424603
20.  Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9-10 year old children in South-India1-3 
The Journal of nutrition  2010;140(5):1014-1022.
Folate and vitamin B-12 (B-12) are essential for normal brain development. Few studies have examined the relationship of maternal folate and B-12 status during pregnancy to offspring cognitive function. To test the hypothesis that lower maternal plasma folate and B-12 concentrations and higher plasma homocysteine concentrations during pregnancy, are associated with poorer neurodevelopment, cognitive function was assessed during 2007-2008 among 536 children (aged 9-10 y) from the Mysore Parthenon birth cohort. Maternal folate, B-12 and homocysteine concentrations were measured in stored plasma samples taken at 30±2 wk gestation. The children’s cognitive function was measured using 3 core tests from the Kaufman Assessment Battery and additional tests measuring learning ability, long-term storage/retrieval, attention and concentration, visuo-spatial and verbal abilities. During pregnancy 4% of mothers had low folate concentrations (<7 nmol/L), 42.5% had low B-12 concentrations (<150 pmol/L) and 3% had hyperhomocysteinemia (>10 μmol/L). There was a 0.1-0.2 SD increase in the children’s cognitive scores per SD increase in maternal folate concentration (p<0.001 for all tests). The associations with learning ability and long-term storage/retrieval, visuo-spatial ability, attention and concentration were independent of maternal age, BMI, parity, the parents’ education, socio-economic status, rural/urban residence, religion, the child’s gestational age, birth size, sex and the children’s size, educational level and folate and B-12 concentrations at 9.5 y. There were no consistent associations of maternal B-12 and homocysteine concentrations with childhood cognitive performance.
In this Indian population higher maternal folate, but not vitamin B-12 concentrations during pregnancy, predicted better childhood cognitive ability.
PMCID: PMC3672847  PMID: 20335637
21.  [No title available] 
PMCID: PMC3644809  PMID: 10736356
22.  Alignment of the Transcription Start Site Coincides with Increased Transcriptional Activity from the Human Asparagine Synthetase Gene Following Amino Acid Deprivation of HepG2 Cells1 
The Journal of nutrition  2006;136(10):2463-2467.
Transcription initiation sites of the asparagine synthetase gene were investigated in human hepatoma cells after amino acid limitation by incubation in amino acid-complete minimal essential medium or medium lacking histidine. Cells incubated in complete minimal essential medium had mRNA transcripts with starting positions spanning across the 69 nucleotides immediately upstream of a previously designated transcription start site (+1), whereas the majority of mRNA transcripts started at nucleotide +1 in cells incubated in histidine-free medium. Similar results were obtained regardless of whether the analysis was by 5′ rapid amplification of cDNA ends or a ribonuclease protection assay. Low ASNS mRNA expression in amino acid-complete medium was associated with the wide range of initiation sites, whereas preferred alignment of the general transcription machinery at nucleotide +1, observed in the amino acid deprived condition, was associated with a concurrent increase in transcription activity. To our knowledge, these results are the first example in a mammalian cell of transcription start selection by nutrient availability.
PMCID: PMC3595576  PMID: 16988110
23.  Increases in Plasma Holotranscobalamin Can Be Used to Assess Vitamin B-12 Absorption in Individuals with Low Plasma Vitamin B-12123 
The Journal of nutrition  2009;139(11):2119-2123.
Low plasma concentrations of vitamin B-12 are common in Indians, possibly due to low dietary intakes of animal-source foods. Weather malabosrption of the vitamin contributes to this has not been investigated. A rise in plasma holotranscobalamin (holo-TC) concentration after a standard dose of oral vitamin B-12 has been proposed as a measure of gastrointestinal absorption in people with normal plasma vitamin B-12 concentrations. We studied 313 individuals (children and parents, 109 families) in the Pune Maternal Nutrition Study. They received 3 doses of 10 μg (n=191) or 2 μg (n=122) of cyanocobalamin at 6 h intervals. A rise in plasma holo-TC of ≥15% and >15 pmol/L above baseline was considered normal vitamin B-12 absorption. The baseline plasma vitamin B-12 was <150 pmol/L in 48% of participants; holo-TC was <35 pmol/L in 98%, and total homocysteine was high in 50% (>10 μmol/L in children and >15 μmol/L in adults). In 10 μg group plasma holo-TC concentration increased by 4.8 -fold from (mean ± SD) 9.3 ± 7.0 pmol/L to 53.8 ± 25.9 pmol/L, and in 2 μg group by 2.2 -fold from 11.1 ± 8.5 pmol/L to 35.7 ± 19.3 pmol/L. Only 10% of participants, mostly fathers, had an increase less than the suggested cut-points. Our results suggest that an increase in plasma holo-TC may be used to assess vitamin B-12 absorption in individuals with low vitamin B-12 status. Because malabsorption is unlikely to be a major reason for the low plasma vitamin B-12 concentrations in this population, increasing dietary vitamin B-12 should improve their status.
PMCID: PMC3428886  PMID: 19776185
Vitamin B-12; cyanocobalamin; holotranscobalamin; absorption; India
24.  Preschool-Aged Children with Iron Deficiency Anemia Show Altered Affect and Behavior1,2 
The Journal of Nutrition  2007;137(3):683-689.
This study compared social looking and response to novelty in preschool-aged children (47–68 mo) with or without iron deficiency anemia (IDA). Iron status of the participants from a low-income community in New Delhi, India, was based on venous hemoglobin, mean corpuscular volume, and red cell distribution width. Children’s social looking toward adults, affect, and wary or hesitant behavior in response to novelty were assessed in a semistructured paradigm during an in-home play observation. Affect and behavior were compared as a function of iron status: IDA (n = 74) vs. nonanemic (n = 164). Compared with nonanemic preschoolers, preschoolers with IDA displayed less social looking toward their mothers, moved close to their mothers more quickly, and were slower to display positive affect and touch novel toys for the first time. These results indicate that IDA in the preschool period has affective and behavioral effects similar to those reported for IDA in infancy.
PMCID: PMC3311027  PMID: 17311960
25.  Skeletal Muscle Protein Anabolic Response to Increased Energy and Insulin Is Preserved in Poorly Controlled Type 2 Diabetes12 
The Journal of nutrition  2006;136(5):1249-1255.
Type 2 diabetes (T2DM) subjects failing diet treatment are characterized by hyperinsulinemia and insulin resistance leading to fasting and postprandial hyperglycemia and hyperlipidemia. Energy is essential for allowing the process of protein synthesis to proceed. Additionally, insulin can stimulate protein synthesis in human muscle. The aims of this study were to determine if poorly controlled T2DM affects postabsorptive muscle protein anabolism, and if the muscle anabolic response to hyperinsulinemia with high energy availability is maintained. Control (n = 6) and T2DM subjects (n = 6) were studied in the postabsorptive state and during an isoenergetic high nutritional energy clamp (relative to postabsorptive state). Muscle protein synthesis and breakdown (nmol · min−1 · 100 g leg muscle−1) were assessed using stable isotope methodology, femoral arterio-venous sampling, muscle biopsies, and a three-pool model to calculate protein turnover. Postabsorptive phenylalanine net balance and whole body rate of appearance (Ra) were not different between groups; however, basal muscle protein breakdown was higher in T2DM (94 ± 9) than in controls (58 ± 12) (P < 0.05) and muscle protein synthesis tended (P = 0.07) to be elevated in T2DM (66 ± 14) compared with controls (39 ± 6). During the clamp, net balance increased, whole body Ra and muscle protein breakdown decreased (P < 0.05), and muscle protein synthesis tended to decrease (P = 0.08) to a similar extent in both groups. We conclude that postabsorptive muscle protein turnover is elevated in poorly controlled T2DM, however, there is no excessive loss of muscle protein because net balance is not different from controls. Moreover, the anabolic response to increased insulin and energy availability is maintained in T2DM.
PMCID: PMC3196634  PMID: 16614412
type 2 diabetes; protein metabolism; muscle protein synthesis; protein turnover

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