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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE225568 | GEO | 2023/11/08

REPOSITORIES: GEO

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Project description:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. The protocols and data of the murine study of de novo lipogenesis are included in the study MTBLS614. Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS614' target='_blank'>MTBLS614</a>

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

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