Gestational folic acid content alters the development and function of hypothalamic food intake regulating neurons in Wistar rat offspring post-weaning

2018 ◽  
Vol 23 (2) ◽  
pp. 149-160 ◽  
Author(s):  
Neil Victor Yang ◽  
Emanuela Pannia ◽  
Diptendu Chatterjee ◽  
Ruslan Kubant ◽  
Mandy Ho ◽  
...  
Keyword(s):  
Folic Acid ◽  
Food Intake ◽  
Acid Content ◽  
Wistar Rat ◽  
Rat Offspring ◽  
And Function

scholarly journals Choline and Folic Acid Balance in Diets During Pregnancy Programs Food Intake Regulation in Wistar Rat Offspring (FS08-05-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Rola Hammoud ◽  
Chih-Sheng Liao ◽  
Emanuela Pannia ◽  
Mandy Ho ◽  
Neil Yang ◽  
...  
Keyword(s):  
Body Weight ◽  
Folic Acid ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Control Diet ◽  
Wistar Rat ◽  
Rat Offspring ◽  
Food Intake Regulation ◽  
Intake Regulation

Abstract Objectives High gestational folic acid (FA) induces an obesogenic phenotype in male Wistar rat offspring. Imbalances between FA and other methyl-nutrients (i.e., choline) leading to perturbations in the 1-carbon cycle may account for the effects of high FA diets. Canadian women consume high (2–7-fold) intakes of FA, but most are not meeting recommended adequate intakes for choline. Choline is also absent from Canadian prenatal supplements. The objective of this study is to evaluate the effects of the interaction between choline and FA in maternal diets of rats on the 1-carbon cycle, and the programming of food intake, body weight gain and biomarkers of obesity in the offspring later in life. Methods Pregnant Wistar rat dams were fed the AIN-93 G diet with recommended (1X) choline and FA (RCRF, control), or a 5X FA diet with either 0.5X choline (LCHF), 1X choline (RCHF), or 2.5X choline (HCHF). Brain and blood were collected at birth. At weaning one male pup/dam from all groups was maintained on the control diet for 20 weeks then terminated. Dependent measures include weekly body weight-gain and food intake, plasma glucoregulatory hormones and 1-carbon metabolites at birth and post-weaning. Results Increasing choline content to 2.5-fold in a high (5-fold) gestational FA diet (HCHF) led to lower plasma insulin and leptin levels at birth compared to the LCHF and RCHF diets, respectively (P < 0.05). It also led to lower (25%, P = 0.03) plasma 5-methyltetrahydrofolate concentrations at birth compared to the RCHF diet, suggesting more efficient utilization of FA. Offspring born to dams maintained on a high folic acid diet with either low or recommended choline had higher weekly food intake (6%, P < 0.05) and body weight-gain (9%, P < 0.01). In contrast, offspring from dams fed the HCHF gestational diet were not different from those born to dams fed the RCRF (control) diet, highlighting the mitigating effects of a balanced choline and FA gestational diet. Conclusions Increased intakes of choline mitigate the effects of high FA diets. Maternal dietary choline interacts with FA on the long-term programming of food intake regulation in the offspring; emphasizing a need for more attention to improving choline intakes by women of child-bearing age. Funding Sources This research was funded by the Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD).

The effect of high multivitamin diet during pregnancy on food intake and glucose metabolism in Wistar rat offspring fed low-vitamin diets post weaning

2011 ◽  
Vol 2 (5) ◽  
pp. 302-310 ◽  
Author(s):  
I. M. Y. Szeto ◽  
P. S. P. Huot ◽  
S. A. Reza-López ◽  
A. Jahan-mihan ◽  
G. H. Anderson
Keyword(s):  
Metabolic Syndrome ◽  
Food Intake ◽  
Insulin Response ◽  
Fold Increase ◽  
Wistar Rat ◽  
Oral Glucose ◽  
Glucose Response ◽  
Rat Offspring ◽  
Vitamin Content ◽  
The Metabolic Syndrome

Rat offspring born to dams fed a high multivitamin diet (HV) are shown to have increased risks of obesity and metabolic syndrome. We hypothesized that a low-vitamin postweaning diet would enhance these characteristics in offspring born to HV dams. During pregnancy, Wistar rats were fed the AIN-93G diet with or without a 10-fold increase in vitamin content. In Experiment 1, at weaning, males were fed the recommended diet (RV) or a diet with 1/3 the vitamin content (1/3 RV) for 12 weeks. In Experiment 2, males and females were fed the RV diet or 1/6 RV diet for 35 weeks. Body weight was measured on a weekly basis, food intake on a daily basis, and for 1 h after an overnight fast following glucose gavage at 6, 12 and 24 weeks. Blood glucose and insulin responses to an oral glucose load were measured at 30 weeks. Males from HV dams, compared with those from RV dams, gained more weight in Experiment 1 (+7%,P< 0.05) and Experiment 2 (+11%,P< 0.0001), along with higher glucose response (+33%,P< 0.05). The 1/6 RV pup diet led to lower weight gain in males (−16%,P< 0.0001) and females (−13%,P< 0.0005), and lower food intake in males (−9%,P< 0.01) independent of the gestational diet. Females on the 1/6 RV diet and from HV dams had higher 1 h food intake (+36%,P< 0.05) and lower insulin response (−25%,P< 0.05) compared with those from RV dams. Exposure of the offspring to low-vitamin diets did not amplify the expression of the metabolic syndrome observed in those born to dams fed an HV diet.

scholarly journals High 5MTHF, but Not Folic Acid During Pregnancy, Alters Hypothalamic Regulatory Pathways and Associates with Post-Partum Weight-Gain in Wistar Rat Mothers

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1230-1230
Author(s):  
Emanuela Pannia ◽  
Rola Hammoud ◽  
Ruslan Kubant ◽  
Rebecca Simonian ◽  
Zdenka Pausova ◽  
...  
Keyword(s):  
Body Weight ◽  
Folic Acid ◽  
Weight Gain ◽  
Food Intake ◽  
Differentially Expressed Genes ◽  
Hormone Receptor ◽  
Body Weight Gain ◽  
Post Partum ◽  
Wistar Rat ◽  
Regulatory Pathways

Abstract Objectives 5-methyltetrahydrofolate (5MTHF), the bioactive folate form, has been proposed an alternative supplement to folic acid (FA) due to direct cellular uptake and utilization. In North America, 5MTHF is incorporated into prenatal supplements at the equivalent high dose (1000 µg) as FA and discussion has been raised of its formation into baby formula. Our lab was the first to compare the dose (1X vs high, 5X) and form (FA vs 5MTHF) effects of folate during pregnancy on later-life metabolic health of the Wistar rat mother. Contrary to our hypothesis, 5MTHF diets, independent of dose, led to mothers with 40% greater body weight-gain and higher food intake post-birth compared to FA. The objective of this study was to identify differentially expressed genes and related hypothalamic pathways of mothers fed FA vs 5MTHF diets during pregnancy. Methods Pregnant Wistar rats were fed an AIN-93 G diet with recommended (1X, control, 2 mg/kg diet) or high (5X) FA or equimolar levels of 5MTHF. At birth, a subset of dams were terminated and RNA-seq analysis was performed in the arcuate nucleus of the hypothalamus (ARC), a key regulator of body weight and food intake, in dams fed the high FA and MTHF diets. Results Over 350 differentially expressed genes were identified in the ARC of dams fed high 5MTHF vs FA diets. Combining differential gene expression patterns with reported GO function terms and Kegg pathway analyses, four candidate genes (prolactin hormone receptor, corticotropin releasing hormone receptor, KISS1 peptide and dopamine receptor) were validated by qPCR thus far as plausible contributors to higher body weight-gain and food intake in 5MTHF dams. These genes correspond to neuroactive ligand-receptor interaction pathway (path: hsa04080), associated with metabolic diseases including leptin deficiency and genetic obesity. Other significantly enriched pathways included the retrograde endocannabinoid signalling and morphine addiction pathway. Conclusions High 5MTHF supplementation during pregnancy alters expression of central feeding regulatory pathways in the hypothalamus of the mother, potentially programming post-partum body-weight gain. 5MTHF, at the equivalent dose of FA, may not be the preferred folate form during pregnancy. Funding Sources CIHR-INMD; EP supported by NSERC-CGS D.

scholarly journals [6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 48
Author(s):  
Emanuela Pannia ◽  
Rola Hammoud ◽  
Rebecca Simonian ◽  
Erland Arning ◽  
Paula Ashcraft ◽  
...  
Keyword(s):  
Gene Expression ◽  
Folic Acid ◽  
Food Intake ◽  
Rna Sequencing ◽  
Control Diet ◽  
Wistar Rat ◽  
Metabolic Phenotype ◽  
Maternal Metabolism ◽  
Plasma Hormones ◽  
Plasma Leptin

[6S]-5-methyltetrahydrofolic acid (MTHF) is a proposed replacement for folic acid (FA) in diets and prenatal supplements. This study compared the effects of these two forms on maternal metabolism and hypothalamic gene expression. Pregnant Wistar rats received an AIN-93G diet with recommended FA (1X, 2 mg/kg, control), 5X-FA or equimolar levels of MTHF. During lactation they received the control diet and then a high fat diet for 19-weeks post-weaning. Body weight, adiposity, food intake, energy expenditure, plasma hormones, folate, and 1-carbon metabolites were measured. RNA-sequencing of the hypothalamus was conducted at parturition. Weight-loss from weaning to 1-week post-weaning was less in dams fed either form of the 5X vs. 1X folate diets, but final weight-gain was higher in 5X-MTHF vs. 5X-FA dams. Both doses of the MTHF diets led to 8% higher food intake and associated with lower plasma leptin at parturition, but higher leptin at 19-weeks and insulin resistance at 1-week post-weaning. RNA-sequencing revealed 279 differentially expressed genes in the hypothalamus in 5X-MTHF vs. 5X-FA dams. These findings indicate that MTHF and FA differ in their programing effects on maternal phenotype, and a potential adverse role of either form when given at the higher doses.

scholarly journals Maternal and postweaning folic acid supplementation interact to influence body weight, insulin resistance, and food intake regulatory gene expression in rat offspring in a sex-specific manner

2016 ◽  
Vol 41 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Pedro S.P. Huot ◽  
Anna Ly ◽  
Ignatius M.Y. Szeto ◽  
Sandra A. Reza-López ◽  
Daniel Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Body Weight ◽  
Folic Acid ◽  
Acid Content ◽  
Maternal Diet ◽  
Folic Acid Supplementation ◽  
Acid Supplementation ◽  
Rat Offspring ◽  
Specific Manner

Maternal intake of multivitamins or folic acid above the basal dietary requirement alters the growth and metabolic trajectory of rat offspring. We hypothesized that a modest increase in the folic acid content of maternal diets would alter the offspring’s metabolic phenotype, and that these effects could be corrected by matching the folic acid content of the offspring’s diet with that of the maternal diet. Female Sprague–Dawley rats were placed on a control or a 2.5× folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, pups from each maternal diet group were randomized to the control or to the 2.5× folic acid-supplemented diet for 25 weeks. Male pups from dams fed the folic acid-supplemented diet were 3.7% heavier than those from control-fed dams and had lower mRNA expression for leptin receptor Obrb isoform (Lepr) (11%) and Agouti-related protein (Agrp) (14%). In contrast, female pups from folic acid-supplemented dams were 5% lighter than those from control-fed dams and had lower proopiomelanocortin (Pomc) (42%), Lepr (32%), and Agrp (13%), but higher neuropeptide Y (Npy) (18%) mRNA expression. Folic acid supplementation ameliorated the alterations induced by maternal folic acid supplementation in male pups and led to the lowest insulin resistance, but the effects were smaller in female pups and led to the highest insulin resistance. In conclusion, maternal folic acid supplementation at 2.5× the control level was associated with alterations in body weight and hypothalamic gene expression in rat offspring in a sex-specific manner, and some of these effects were attenuated by postweaning folic acid supplementation.

scholarly journals High Choline During Pregnancy Reduces Characteristics of the Metabolic Syndrome in Male Wistar Rat Offspring Fed a High Fat Post-Weaning Diet

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1313-1313
Author(s):  
Rola Hammoud ◽  
Emanuela Pannia ◽  
Ruslan Kubant ◽  
Rebecca Simonian ◽  
G Harvey Anderson
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Wistar Rat ◽  
Visceral Adiposity ◽  
Metabolic Phenotype ◽  
Energy Regulation ◽  
High Fat ◽  
Rat Offspring ◽  
Postnatal Environment

Abstract Objectives The prenatal period is a critical time for fetal development, programming the offspring's later-life health in response to the postnatal environment. We have shown that a high maternal choline diet programs long-term energy regulation leading to higher food intake and weight-gain in mature rat offspring fed a normal fat diet. However, the offspring's response to an obesogenic post-weaning diet has not been described. We aim to elucidate the interaction between the choline content of the gestational diet (GD) and fat content of the post-weaning diet (PWD) on male Wistar rat offspring's long-term metabolic phenotype. Methods Pregnant Wistar rats were fed an AIN-93G diet with either recommended choline (RC, 1g/kg diet choline bitartrate) or high choline (HC, 2.5-fold). Male pups were weaned to either a normal (10%) fat (RC-NF and HC-NF) or a high (45%) fat (RC-HF and HC-HF) diet for 17 weeks. Dependent measures were body weight, food intake, visceral adiposity, plasma glucoregulatory hormones and triglycerides, and plasma and hepatic free fatty acids (FFAs). Data were analyzed with 2-way ANOVA for main effects of GD and PWD and their interaction. Measures with significant interaction effects were followed by a Student's T-test comparing groups stratified by PWD. Results HC-HF offspring had lower body weight (7%, P &lt; 0.05), and visceral adiposity (15%, P &lt; 0.05), but no difference in food intake compared to RC-HF. HC-HF offspring had lower insulin (18%, P &lt; 0.05), HOMA-IR (24%, P &lt; 0.01), and plasma triglycerides (30%, P &lt; 0.05) but no difference in leptin. Total hepatic ω-3 FFAs (30%, P &lt; 0.05) were higher and ω-6/ω-3 (P &lt; 0.01) was lower in HC-HF compared to RC-HF, indicating an ameliorated metabolic phenotype in HC-HF offspring. In contrast, HC-NF offspring had higher food intake (8%, P &lt; 0.01) and body weight (6%, P &lt; 0.05) and no difference in adiposity compared to RC-NF. They also had higher plasma leptin adjusted for adiposity (22%, P &lt; 0.05) but not insulin or HOMA-IR compared to RC-NF. Hepatic C16:1n-7/C16:0 ratio was higher in HC-NF compared to RC-NF, suggestive of dysregulated lipid metabolism. Conclusions Gestational choline supplementation is associated with improved long-term metabolic regulation in male Wistar rat offspring fed a high fat post-weaning diet. Funding Sources CIHR-Institute of Nutrition, Metabolism, and Diabetes.

scholarly journals Maternal Choline Intake Programs Hypothalamic Energy Regulatory Pathways and Long-Term Phenotype in Male Wistar Rat Offspring (OR35-04-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Rola Hammoud ◽  
Emanuela Pannia ◽  
Chih-Sheng Liao ◽  
Diptendu Chatterjee ◽  
Mandy Ho ◽  
...  
Keyword(s):  
Weight Gain ◽  
Food Intake ◽  
Energy Expenditure ◽  
Wistar Rat ◽  
In Utero ◽  
Receptor Expression ◽  
Rat Offspring ◽  
Choline Intake ◽  
Energy Regulatory

Abstract Objectives The prenatal period is a critical time of brain development. Maternal choline intake is associated with improvement in memory and cognitive function in the offspring. However, the role of choline in the regulation of physiological functions controlled by the hypothalamus has not been reported. The objective of this study is to elucidate the effects of choline intake on the in utero programming of hypothalamic energy regulatory neurons in male Wistar rat offspring. Methods Pregnant Wistar rats received an AIN-93G diet containing recommended choline (RC, 1 g/kg diet), low choline (LC, 0.5-fold), or high choline (HC, 2.5-fold). At birth, brain and blood was collected from male pups. Male pups from each dietary treatment were maintained on the control diet for 17-weeks. Dependent measures include post-weaning food intake, energy expenditure, weight-gain, plasma glucoregulatory hormones, brain choline and 1-carbon metabolite levels, and expression of hypothalamic energy regulatory neurons. Results At birth, pup brain concentrations of choline proportionally reflected the choline content in the maternal diets. HC pups had higher hypothalamic protein expression of the orexigenic neuropeptide-Y neuron than both groups (P < 0.05), but lower activation than LC pups (P < 0.05). Both HC and LC pups had lower plasma leptin concentrations than RC pups (P < 0.01), but LC pups had lower hypothalamic leptin receptor expression compared to both groups at birth (P < 0.05). During adulthood, offspring of HC dams had higher weekly food intake compared to RC (11%, P < 0.01), and higher weight-gain than both RC and LC groups (12%, P < 0.05). LC offspring had lower 24hr energy expenditure and locomotor activity than HC and RC groups (6%, P < 0.05). Conclusions Choline content of diets consumed by rats during pregnancy impacts in utero development of hypothalamic energy regulatory systems; long-term body weight-gain, food intake and energy expenditure in mature rat offspring. Funding Sources This research was supported by the Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD).

Folic acid content of diet during pregnancy determines post-birth re-set of metabolism in Wistar rat dams

2020 ◽  
Vol 83 ◽  
pp. 108414 ◽  
Author(s):  
Emanuela Pannia ◽  
Neil V. Yang ◽  
Mandy Ho ◽  
Diptendu Chatterjee ◽  
Rola Hammoud ◽  
...  
Keyword(s):  
Folic Acid ◽  
Acid Content ◽  
Wistar Rat

scholarly journals Dietary Intakes of Folic Acid During Pregnancy Determines Maternal Re-Set of Metabolism Post-Birth in Wistar Rat Dams (FS08-06-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Emanuela Pannia ◽  
Neil Yang ◽  
Mandy Ho ◽  
Rola Hammoud ◽  
Ruslan Kubant ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Folic Acid ◽  
Food Intake ◽  
Metabolic Pathways ◽  
Wistar Rat ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Maternal Metabolism ◽  
Carbon Pathways

Abstract Objectives Nutrition during pregnancy alters the “re-set” of maternal metabolism and in turn the mother's metabolic phenotype later in life. Folic acid (FA, synthetic folate) consumed at intakes above requirements during pregnancy by rats leads to increased weight gain and altered DNA methylation in central and peripheral pathways regulating food intake. The objectives of this study were to examine the effects of intakes below and above FA dietary requirements on the re-set of energy metabolic pathways in Wistar rat mothers early post-birth. Methods Pregnant Wistar rats (n = 12/group) were fed an AIN93G diet with 5 levels of FA: 0X, 1X (control, 2 mg FA/kg), 2.5X, 5X or 10X. Dams were fed 1X-FA during lactation up to 1-week post-weaning (PW) when maternal metabolism is thought to re-set to homeostasis and then terminated. Weekly body weight, food intake, expression of hypothalamic food-intake neurons, mRNA and protein expression of folate-related and energy metabolic genes, and glucoregulatory hormones were measured. The homeostatic model assessment of insulin resistance (HOMA-IR) was used as a surrogate index of insulin resistance. Results Below (0X) and above (5X and 10X) FA requirements during pregnancy suppressed expression of hepatic folate metabolism (methyltetrahydrofolate (MTHF) reductase, and methionine synthase; P < 0.05) genes and led to higher 5-MTHF (P < 0.005) in blood compared to control suggesting dysregulation of 1-carbon pathways. Dams fed 0X- and 5X-FA also had higher plasma insulin and HOMA-IR than controls and changes in glucose and lipid metabolism-regulating genes in muscle (Glucose transporter-4, and Peroxisome-proliferator activated receptors; P < 0.05) but not liver or adipose at 1-week PW. The diets did not affect expression of hypothalamic food intake neurons nor body weight or food intake of the dams from birth to 1-week PW. Conclusions FA below (0X) or above (5X, 10X) requirements during pregnancy induce dysregulation of 1-carbon pathways and delay re-set of energy metabolic pathways in Wistar rat dams by 4-weeks after birth, potentially programming long-term negative metabolic effects. Funding Sources This research was supported by: Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD); EP supported by NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program (CGS D).

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