Folic Acid Content in Gestational Diet Elicits Dose‐dependent Changes on Hypothalamic Feeding Circuits in Wistar Rats at Birth
Bibliographic record
Abstract
Background Folate plays an important role in early brain development of offspring, notably on neural stem cell proliferation and differentiation. Excess (10‐fold) intakes of folic acid (FA) in the gestational diet have been linked to increased food intake and obesity in adult offspring. Hypothalamic neuronal populations play a critical role in regulating food intake and maintaining energy balance. Objectives To identify neuronal populations susceptible to FA intakes during pregnancy, we measured the expression and maturation of neuropeptide Y (NPY + ) and proopiomelanocortin (POMC + ) containing neurons, known to induce opposing effects on food intake regulation. Furthermore, we tested if these outcomes could be explained by altered folate metabolism in the brain, which could lead to epigenetic reprogramming of neuronal differentiation and maturation. Methods and Design Pregnant Wistar rats were assigned to one of 5 AIN‐93G diets (n=12/group) providing FA at: 0, 1.0 (control), 2.5, 5.0, or 10.0‐fold of recommended level. Expression of NPY and POMC neuronal populations were assessed in coronal hypothalamic sections from male rat offspring, collected at birth. Immunohistochemical staining for the neuronal nuclear antigen (NeuN) measured neuron quantity and maturation. Hypothalamic levels of folate metabolites were assessed by HPLC analysis. Results A dose‐dependent effect ( P <0.05) was identified between higher intakes of gestational FA and increased expression of mature NPY‐containing neurons in the hypothalamus, at birth. Pups from 2.5‐ and 5.0‐fold FA groups had 2.2 and 3.1‐fold more mature NPY‐neurons than control, respectively. However, gestational FA content had no effect on the number and maturation of POMC‐expressing neurons. Deficient (0‐fold) and high (10.0‐fold) FA gestational diets lead to higher levels of tetrahydrofolate (THF, 2.4 fold, P <0.0001) and 5‐methyltetrahydrofolate (MTHF, 3–4 fold, P <0.0001) in the hypothalamus, compared to control. Conclusion FA content in the gestational diet elicits a dose‐dependent effect on the number of mature hypothalamic NPY neurons in male Wistar rats at birth, possibly associated with greater accumulation of folate metabolites in the brain. This indicates that hypothalamic food intake pathways are sensitive to the dose of gestational FA and its bioactive metabolites, which may influence metabolic phenotype of offspring later in life. Support or Funding Information Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR‐INMD), Reference MOP‐130286.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".