Ketogenic diet leads to O-GlcNAc modification in the BTBRT+tf/j mouse model of autism.

Abstract

BACKGROUND:

Protein O-linked-β-N-acetyl glucosamine (O-GlcNAc) is a post-translational modification to Ser/Thr residues that integrates energy supply with demand. Abnormal O-GlcNAc patterning is evident in several neurological disease states including epilepsy, Alzheimer's disease and autism spectrum disorder (ASD). A potential treatment option for these disorders includes the high-fat, low-carbohydrate, ketogenic diet (KD). The goal of this study was to determine whether the KD induces changes in O-GlcNAc in the BTBRT+tf/j (BTBR) mouse model of ASD.

METHODS:

Juvenile male (5weeks), age-matched C57 or BTBR mice consumed a chow diet (13% kcal fat) or KD (75% kcal fat) for 10-14days. Following these diets, brain (prefrontal cortex) and liver were examined for gene expression levels of key O-GlcNAc mediators, global and protein specific O-GlcNAc as well as indicators of energy status.

RESULTS:

The KD reduced global O-GlcNAc in the livers of all animals (p<0.05). Reductions were likely mediated by lower protein levels of O-GlcNAc transferase (OGT) and increased O-GlcNAcase (OGA) (p<0.05). In contrast, no differences in global O-GlcNAc were noted in the brain (p>0.05), yet OGT and OGA expression (mRNA) were elevated in both C57 and BTBR animals (p<0.05).

CONCLUSIONS:

The KD has tissue specific impacts on O-GlcNAc. Although levels of O-GlcNAc play an important role in neurodevelopment, levels of this modification in the juvenile mouse brain were stable with the KD despite large fluctuations in energy status. This suggests that it is unlikely that the KD exerts it therapeutic benefit in the BTBR model of ASD by O-GlcNAc related pathways.

• Authors: Christopher Newell, Virginia L Johnsen, Nellie C Yee, Warren J Xu, Matthias S Klein, Aneal Khan, Jong M Rho, Jane Shearer
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1863 Issue 9 Pg. 2274-2281 (09 2017) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28502704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Nerve Tissue Proteins
• Acetylglucosamine

Topics

• Acetylglucosamine (genetics, metabolism)
• Animals
• Autistic Disorder (genetics, metabolism, pathology)
• Diet, Ketogenic
• Disease Models, Animal
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Prefrontal Cortex (metabolism, pathology)
• Protein Processing, Post-Translational