Upregulated Hepatic Lipogenesis from Dietary Sugars Supplies Palmitic Acid to the Developing Brain of Mice fed Low Palmitic Acid from Birth

Background: Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL) primarily from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results on the origin of adult brain PAM. Here, we utilize naturally occurring carbon isotope ratios (13C/12C; δ13C) and RNA sequencing to uncover the origin of brain PAM, and pathways involved in maintaining brain PAM, respectively, during development. maintaining brain PAM, respectively, during development. Methods: Dams were equilibrated onto diets low (<2%), medium (47%) or high (>95%) in PAM prior to breeding. Dietary PAM was depleted in δ13C, while dietary sugars were enriched. Offspring stayed on the respective dam diet and were euthanized at postnatal day 0, 10, 21, and day 35. Pup liver and brain fatty acids were quantified, after which, tissue δ13C-PAM was measured by compound specific isotope analysis. Day 35 tissue RNA was sequenced on a NovaSeq S4 Flowcell. Results: Although PAM levels in the liver reflected levels of dietary PAM, PAM was maintained in total and individual brain phospholipid fractions across diet groups at all timepoints. Tissue δ13C-PAM was enriched overall and augmented in mice fed low PAM, compared to medium and high PAM suggesting that DNL from dietary sugars maintained the majority of the brain PAM pool. Furthermore, DNL pathways were upregulated in mice fed low compared to high PAM in the liver, but not the brain at day 35. Conclusions: Lipogenesis from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM from birth. Importantly, hepatic lipogenesis from dietary sugars determines PAM availability to the developing brain when low in the diet – a compensatory mechanism identified to maintain total brain PAM pools compared to periphery which ultimately suggests an importance of brain PAM regulation during development. Pairwise comparisons of RNAseq data of brain and liver tissue from 35-day old BALB/c mice fed custom diets containing low (<2%), medium (~47%) and high (>95%) PAM