Maternal vitamin D deficiency during pregnancy affects expression of adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (PPARγ) and vitamin D receptor (VDR) in lean male mice offspring.

PURPOSE: Maternal vitamin D deficiency during pregnancy is a widespread issue that may have long-lasting consequences on offspring adiposity. We sought to determine how maternal vitamin D deficiency during the perinatal period would affect offspring adipose tissue development and gene expression. METHODS: Female C57BL/6 J mice were fed either a vitamin D deficient (VDD) or control diet from 4 weeks before pregnancy (periconception) until 7 days postparturition. Male offspring were weighed and euthanized at 75 days of age (early adult period), at which point serum was collected for biochemical analyses, and perigonadal and subcutaneous white adipose tissue (PGAT and SQAT, respectively) were excised, weighed, then flash-frozen for later histology and analyses of adipogenic gene expression. RESULTS: All adult male offspring were nonobese; there were no significant differences in body weight, adipose pad weight, or adipocyte size. However, VDD-exposed offspring had greater expression of the adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (Pparg) and vitamin D receptor (Vdr). CONCLUSIONS: This study suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue in nonobese offspring. These novel findings invite further investigation into the mechanisms by which maternal vitamin D status during pregnancy affects adipose development and metabolic health of offspring.

Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder.

Many children and adolescents with autism spectrum disorder (ASD) have significant gastrointestinal (GI) symptoms, but the etiology is currently unknown. Some individuals with ASD show altered reactivity to stress and altered immune markers relative to typically-developing individuals, particularly stress-responsive cytokines including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Acute and chronic stress is associated with the onset and exacerbation of GI symptoms in those without ASD. The present study examined whether GI symptoms in ASD were associated with increases in cortisol, a stress-associated endocrine marker, and TNF-α and IL-6 in response to stress. As hypothesized, a greater amount of lower GI tract symptoms were significantly associated with post-stress cortisol concentration. The relationship between cortisol response to stress and GI functioning was greater for children who had a history of regressive autism. Exploratory analyses revealed significant correlations between cortisol response, intelligence, and inappropriate speech. In contrast, symptoms of the lower GI tract were not associated with levels of TNF-α or IL-6. Significant correlations were found, however, between TNF-α and IL-6 and irritability, socialization, and intelligence. These findings suggest that individuals with ASD and symptoms of the lower GI tract may have an increased response to stress, but this effect is not associated with concomitant changes in TNF-α and IL-6. The relationship between cortisol stress response and lower GI tract symptoms in children with regressive autism, as well as the relationships between cortisol, IL-6, and intelligence in ASD, warrant further investigation.

Vitamin D deficiency & childhood obesity: a tale of two epidemics.

Obesity and vitamin D deficiency represent two of the most wide-spread health concerns in the United States, especially among children. There is a well-established inverse relationship between vitamin D status and obesity; however, it is unknown as to whether vitamin D deficiency contributes to, or is a consequence of obesity. Based on available research, the positive effects of correcting hypovitaminosis D in obesity seem to be primarily related to its action on glycemic control.

Low Urinary Iodine Concentration Is Associated with Increased Risk for Elevated Plasma Glucose in Females: An Analysis of NHANES 2011-12.

Iodine intake in the US has declined in recent years. Iodine insufficiency increases the risk for inadequate thyroid hormone production and there is growing evidence that sub-clinical hypothyroidism may be disruptive to metabolic health, including insulin resistance (IR). We investigated the association between urinary iodine concentrations (UIC), a measurement of iodine status, and IR in adults. Data from 1286 US adults (≥20 years) in the NHANES 2011-2012 were analyzed. Two subgroups (low = UIC < 100 µg/L and normal = UIC ≥ 100 µg/L) were compared for markers of IR, including fasting plasma glucose (FPG) and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and glycated hemoglobin (HbA1C). Chi-square test, both linear and logistic regression models were used. In males, there were no significant associations between UIC and markers of IR; however, females with normal UIC had greater risks for elevated HOMA-IR (AOR = 0.56, 95% CI= 0.32-0.99) and HbA1C (AOR = 0.56, 95% CI = 0.34-0.90), while females with low UIC had a greater risk for FPG ≥ 5.6 mmol/L (AOR = 1.73, 95% CI = 1.09-2.72). Results only partially support our hypothesis that UIC is associated with the odds of IR in adults. The finding of an increased risk for elevated FPG, a marker of prediabetes, in female adults with low iodine status requires further investigation.

Effects of soy isoflavone consumption on bone structure and milk mineral concentration in a rat model of lactation-associated bone loss.

BACKGROUND: Like menopause, during complete lactation, circulating estrogen concentrations are markedly reduced, resulting in amplified bone resorption. AIM OF STUDY: To investigate the effects of soy isoflavones, common dietary components used to mitigate the bone loss of menopause, on the bone loss associated with lactation. METHODS: Lactating rats were randomized to one of four diets supplemented with different levels of soy isoflavones (0, 2, 4, 8 mg aglycone isoflavone/g protein). Milk was collected from all dams between days 12 and 15 of lactation and was analyzed for calcium, phosphorus and genistein concentrations. Serum and bones from half of the animals from each diet group were taken at weaning and from the remaining half at 4 weeks post-weaning. Bones underwent histomorphometric analysis and serum was used for genistein determinations. RESULTS: Serum genistein and milk concentrations reflected dietary isoflavone dose. Isoflavone intake had no effect on any of the bone changes associated with lactation or recovery. Milk calcium and mineral concentrations were unaffected by dietary isoflavones. CONCLUSIONS: Consumption of soy isoflavones, in levels that can be readily attained through soy foods, have neither protective effects on bone nor deleterious effects on milk quality or quantity during lactation.

Short-term effectiveness of an outcomes research training curriculum within a coordinated program.

The fourth edition of the Commission on Accreditation for Dietetics Education Standards of Education mandated outcomes research training. Our objective was to determine the short-term effectiveness (<5 years) of the outcomes research training curriculum in the Coordinated Program in Dietetics (CP) at the University of Missouri-Columbia, which exceeds these minimum standards. Toward this end, a survey tool was administered to University of Missouri-Columbia CP graduates before the implementation of the fourth edition of Standards of Education and to University of Missouri-Columbia CP graduates with two semesters of outcomes research training; graduates of two other CPs from different universities from the same years were also surveyed. Graduates who went through CPs after implementation of the fourth edition of the Standards of Education showed notable improvement in attitudes, interest, and participation in most of the outcomes research skills queried, compared with those who completed their education under the earlier standards; knowledge was only slightly improved. Of these areas, only enhancements in attitudes and interest were consistently more pronounced in food and nutrition professionals trained using the University of Missouri-Columbia's outcomes research curriculum compared with other CP graduates. Both the Commission on Accreditation for Dietetics Education and program directors can use the findings described herein to further assess and develop the research competencies and/or to strengthen their programs.

Lack of skeletal effect of soy isoflavones in intact growing, female rats may be explained by constant serum estrogenic activity despite reduced serum estradiol.

BACKGROUND/AIMS: Scarce data exist on the effects of soy isoflavones (IF) on bone during peripuberty, a known 'window of opportunity' for bone consolidation. Our aim was to determine the skeletal, reproductive, and serum estradiol (E(2))/estrogenic activity response of consuming naturally-occurring soy protein-associated IF during peripuberty. METHODS: Weanling (approximately 3 weeks old), female rats were placed on one of four nutritionally-complete dietary regimens in which protein (200 g/kg diet) was provided as casein or soy protein isolates containing either 0.11 (Low IF), 2.16 (Med IF), or 3.95 (High IF) mg total aglycone isoflavones/g protein for 8 weeks, during which body weights and estrus cycling were recorded. RESULTS: Bone growth and density were unaffected by soy intake while the reproductive tissues showed a slight response (greater uterine weights of the Med and High IF groups). Despite suppression of E(2) concentrations in the High IF group, total circulating estrogenic activity was unaltered. Moreover, in the High IF group, E(2) was significantly depressed compared with bioassayable estrogenic activity, suggesting negative feedback inhibition of E(2) by the elevated circulating levels of IF. CONCLUSIONS: This suppression in E(2) with maintenance of total serum estrogenicity in the High IF group may explain the lack of effect observed in the skeletal tissues.

Molybdenum.

Molybdenum, a trace element essential for micro-organisms, plants, and animals, was discovered in 1778 by a Swedish chemist named Karl Scheele. Initially mistaken for lead, molybdenum was named after the Greek work molybdos, meaning lead-like. In the 1930s, it was recognized that ingestion of forage with high amounts of molybdenum by cattle caused a debilitating condition. In the 1950s, the essentiality of molybdenum was established with the discovery of the first molybdenum-containing enzymes. In humans, only 4 enzymes requiring molybdenum have been identified to date: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime-reducing component (mARC). Sulfite oxidase, an enzyme found in mitochondria, catalyzes oxidation of sulfite to sulfate, the final step in oxidation of sulfur amino acids (cysteine and methionine). Xanthine oxidase converts hypoxanthine to xanthine, and further converts xanthine to uric acid, preventing hypoxanthine, formed from spontaneous deamination of adenine, from leading to DNA mutations if paired with cytosine in place of thymine. Aldehyde oxidase is abundant in the liver and is an important enzyme in phase 1 drug metabolism. Finally, mARC, discovered less than a decade ago, works in concert with cytochrome b5 type B and NAD(H) cytochrome b5 reductase to reduce a variety of N-hydroxylated substrates, although the physiologic significance is still unclear. In the case of each of the molybdenum enzymes, activity is catalyzed via a tricyclic cofactor composed of a pterin, a dithiolene, and a pyran ring, called molybdenum cofactor (MoCo) (1).

Time Course of Vitamin D Depletion and Repletion in Reproductive-age Female C57BL/6 Mice.

The use of animal models in vitamin D deficiency (VDD) research, particularly in regard to maternal deficits, has increased dramatically, yet these studies may be confounded due to ill-conceived experimental timelines. We conducted 2 experiments to (1) characterize the time course of VDD induction and repletion and (2) explore the long-term consequences of VDD on calcium homeostasis and body composition in reproductive-age female mice. Eight-week-old female C57BL/6 mice were randomized to receive either a vitamin D sufficient (VDS) or VDD diet; serum was collected weekly. At week 4, VDD mice were switched to VDS diet, and serum was collected weekly until week 8. Another group of same-age female mice was maintained on VDD diet for 40 wk. Body weights and serum were collected every 2 wk until week 40, when body composition was measured by using echoMRI. Mice did not become VDD until week 3 of the VDD diet and, after decreasing slightly at 4 wk, serum 25-hydroxyvitamin D remained unchanged through 40 wk. Vitamin D repletion to 25-hydroxyvitamin D concentrations considered adequate by the Institute of Medicine took 2 to 3 wk. Prolonged VDD in mice was marked by hypocalcemia and hyperparathyroidism and led to proportional decreases in both lean and fat mass. These data provide guidance in the design of studies using mice as a maternal VDD model, especially those exploring its effects on the developmental origins of health and disease and highlight the importance of monitoring and controlling the calciotropic effects of diet-induced VDD. This study also shows that prolonged VDD in reproductive-age female C57BL/6 mice induces metabolically meaningful changes in absolute, but not relative, body composition.

In utero vitamin D deficiency predisposes offspring to long-term adverse adipose tissue effects.

The fetal period represents an important window of susceptibility for later obesity and metabolic disease. Maternal vitamin D deficiency (VDD) during pregnancy is a global concern that may have long-lasting consequences on offspring metabolic health. We sought to determine whether a VDD in utero environment affects fetal adipose tissue development and offspring metabolic disease predisposition in adulthood. Furthermore, we sought to explore the extent to which the VDD intrauterine environment interacts with genetic background or postnatal environment to influence metabolic health. Eight-week-old P0 female C57BL/6J mice were fed either a VDD diet or sufficient diet (VDS) from four weeks before pregnancy (periconception) then bred to male Avy/a mice. Females were maintained on the diets throughout gestation. At weaning, Avy/a and a/a male F1 offspring were randomized to low-fat (LFD) or high-fat diet (HFD) until 19 weeks of age, at which point serum and adipose tissue were harvested for analyses. Mice born to VDD dams weighed less at weaning than offspring born to VDS dams but experienced rapid weight gain in the four weeks post weaning, and acquired a greater ratio of perigonadal (PGAT) to subcutaneous (SQAT) than control offspring. Additionally, these mice were more susceptible to HFD-induced adipocyte hypertrophy. Offspring of VDD dams also had greater expression of Pparg transcript. These novel findings demonstrate that in utero VDD, an easily correctable but highly prevalent health concern, predisposes offspring to long-term adipose tissue consequences and possible adverse metabolic health complications.

Use of an outcomes research collaborative training curriculum to enhance entry-level dietitians' and established professionals' self-reported understanding of research.

This project pilot tests a unique outcomes research training curriculum that prepares entry-level dietitians (goal 1) and provides established dietetics professionals with the resources to successfully execute an outcomes research plan (goal 2). The learning objectives for each goal were met via lectures and assignments in two courses, one taught in the fall and one in the winter semester of the second (senior) year of the Coordinated Program at the University of Missouri. At their respective healthcare facilities, registered dietitian (RD) preceptors along with the students progressed through all stages of the research process, from proposal development to data presentation. At the completion of the process, a questionnaire was administered to students and preceptors to evaluate the curriculum. Fourteen of the 15 possible student respondents and four of the five possible RD preceptors returned their questionnaires. Salient findings as well as actions to be taken in subsequent course offerings include: (a) clarify expectations, (b) limit geographical distance, (c) increase in-class time, (d) limit project scope, (e) add more statistics training/practice, (f) introduce outcomes research earlier, (g) preceptors' participation was positive. This endeavor allowed us to acquire the information and experience required to make outcomes research training a more significant component of dietetics education.

Lack of multidisciplinary collaboration is a barrier to outcomes research.

OBJECTIVES: To identify and describe methods of collaboration used by dietitians to conduct outcomes research and to identify perceived barriers to participation in outcomes research. DESIGN: A questionnaire was mailed to dietitians to obtain descriptive information about outcomes research involvement. Details of collaborative research experiences were collected in follow-up telephone interviews. SUBJECTS: Subjects were a regional sample of 300 dietitians from the Clinical Nutrition Managers practice group of The American Dietetic Association. One hundred fifty-three subjects (51%) responded to the questionnaire and 25 of 42 eligible respondents were interviewed. ANALYSIS: Frequency counts on questionnaire and closed-ended interview data were analyzed. Chi2 tests were used to identify significant associations between participation in outcomes research and demographic variables. Content analysis of open-ended interview data was used to detect emergence of recurrent themes. RESULTS: Forty-two (27%) respondents had conducted outcomes research. Although all respondents collaborated on at least 1 project, half collaborated only with other dietitians, and 27 of 42 (64%) did not report research findings outside their facility. Interview data suggest that collaboration, especially between disciplines, enhances the entire research process and generates benefits beyond the specific project. The most frequently cited barriers among respondents who had not conducted outcomes research (n=111) were lack of research skills (65%) and lack of time or staff (41%). APPLICATIONS: These findings support the assertion that lack of multidisciplinary involvement is a barrier to generating evidence of nutrition therapy effectiveness. Educators, health care professionals, and dietitians must model and encourage multidisciplinary, collaborative outcomes research in diverse practice settings.

Vitamin D insufficiency and insulin resistance in obese adolescents.

Obese adolescents represent a particularly vulnerable group for vitamin D deficiency which appears to have negative consequences on insulin resistance and glucose homeostasis. Poor vitamin D status is also associated with future risk of type 2 diabetes and metabolic syndrome in the obese. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood, but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation and/or regulation of insulin synthesis/secretion by pancreatic ß cells. Related to the latter, recent data suggest that the active form of vitamin, 1,25-dihydroxyvitamin D, does not impact insulin release in healthy pancreatic islets; instead they require an environmental stressor such as inflammation or vitamin D deficiency to see an effect. To date, a number of observational studies exploring the relationship between the vitamin D status of obese adolescents and markers of glucose homeostasis have been published. Most, although not all, show significant associations between circulating 25-hydroxyvitamn D concentrations and insulin sensitivity/resistance indices. In interpreting the collective findings of these reports, significant considerations surface including the effects of pubertal status, vitamin D status, influence of parathyroid hormone status and the presence of nonalcoholic fatty liver disease. The few published clinical trials using vitamin D supplementation to improve insulin resistance and impaired glucose tolerance in obese adolescents have yielded beneficial effects. However, there is a need for more randomized controlled trials. Future investigations should involve larger sample sizes of obese adolescents with documented vitamin D deficiency, and careful selection of the dose, dosing regimen and achievement of target 25-hydroxyvitamn D serum concentrations. These trials should also include clamp-derived measures of in vivo sensitivity and ß-cell function to more fully characterize the effects of vitamin D replenishment on insulin resistance.

Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial.

BACKGROUND: Obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue. Poor vitamin D status has been associated with a higher prevalence of the metabolic syndrome, type 2 diabetes, or both in adults and adolescents. OBJECTIVE: The objective was to determine in obese adolescents the efficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation. DESIGN: Obese adolescent patients [n = 35; mean ± SD age: 14.1 ± 2.8 y; BMI (in kg/m(2)): 39.8 ± 6.1; 25(OH)D: 19.6 ± 7.1 ng/mL] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were randomly assigned to receive either vitamin D3 (4000 IU/d) or placebo as part of their standard care. Anthropometric measurements, inflammatory markers (IL-6, TNF-α, C-reactive protein), adipokines (leptin, adiponectin), fasting glucose, fasting insulin, and HOMA-IR values were measured at baseline and at 2 follow-up visits (3 and 6 mo). RESULTS: After 6 mo, there were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups. Participants supplemented with vitamin D3 had increases in serum 25(OH)D concentrations (19.5 compared with 2.8 ng/mL for placebo; P < 0.001), fasting insulin (-6.5 compared with +1.2 µU/mL for placebo; P = 0.026), HOMA-IR (-1.363 compared with +0.27 for placebo; P = 0.033), and leptin-to-adiponectin ratio (-1.41 compared with +0.10 for placebo; P = 0.045). Inflammatory markers remained unchanged. CONCLUSION: The correction of poor vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesity and its associated insulin resistance. This trial was registered at clinicaltrials.gov as NCT00994396.

Vitamin d status is not associated with outcomes of experimentally-induced muscle weakness and pain in young, healthy volunteers.

Vitamin D receptors have been identified in skeletal muscle; and symptoms of vitamin D deficiency include muscle weakness and pain. Moreover, increased serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with improved muscle function. To further clarify the importance of vitamin D to muscle, we examined the association between vitamin D status and exercise-induced muscle pain and weakness in healthy people. Muscle damage to the elbow flexors was induced with eccentric exercise (EE) in 48 individuals (22.5 ± 3.2 yrs). Muscle pain ratings following unloaded movement and peak isometric force (IF) were collected before EE and for 4 days post-EE. Linear regression was used to determine if serum 25(OH)D was a predictor of any outcome. In males, R(2)-values from 0.48 to 1.00. R(2) for IF ranged from 0 to 0.02 and P-values from 0.48 to 1.00. In females, R(2) for pain ratings ranged from 0.01 to 0.11 and P-values from 0.14 to 0.59. R(2) for IF ranged from 0 to 0.04 and P-values from 0.41 to 0.90. In conclusion, vitamin D status did not predict muscle pain or strength after EE-induced muscle damage in young healthy men and women.

Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women.

BACKGROUND: Circulating 25 hydroxyvitamin D (25 (OH)D), an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB) light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH) D concentrations) and inflammatory markers in healthy women. METHODS: This observational study included 69 healthy women, age 25-82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OH)D concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OH)D, parathyroid hormone (iPTH), estradiol (E2), cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-alpha), interleukin-6 and -10 (IL-6, IL-10), and C-reactive protein (CRP)]. RESULTS: Women with regular UVB exposure (Hi-D) had serum 25(OH)D concentrations that were significantly higher (p < 0.0001) and iPTH concentrations that were significantly lower (p < 0.0001) than women without regular UVB exposure (Lo-D). Although IL-6, IL-10, and CRP did not have a statistically significant relationship with 25(OH)D concentrations, linear regression models revealed a significant inverse relationship between serum 25(OH)D and TNF-alpha concentrations. This relationship remained significant after controlling for potential covariates such as body fat mass, menopausal status, age, or hormonal contraceptive use. CONCLUSION: Serum 25(OH)D status is inversely related to TNF-alpha concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.