Le régime cétogène conduit à une modification de O-GlcNAc dans le modèle de souris BTBRT + tf / j de l'autisme

Aperçu: G.M.

La protéine O-linked-β-N-acétyl glucosamine (O-GlcNAc) est une modification post-traductionnelle des résidus Ser / Thr qui intègre l'approvisionnement en énergie avec la demande. Le schéma anormal de l'O-GlcNAc est évident dans plusieurs états pathologiques neurologiques, y compris l'épilepsie, la maladie d'Alzheimer et le trouble du spectre de l'autisme (TSA). Une option de traitement potentielle pour ces troubles comprend le régime cétogène à haute teneur en matières grasses et à faible teneur en glucides (KD). L'objectif de cette étude était de déterminer si le KD induit des changements dans O-GlcNAc dans le modèle de souris BTBRT + tf / j (BTBR) du TSA.

Le KD a réduit l'O-GlcNAc global dans le foie de tous les animaux (p <0,05). Les réductions ont probablement été médiées par la diminution des taux de protéines de O-GlcNAc transferase (OGT) et par O-GlcNAcase (OGA) (p <0,05). En revanche, aucune différence dans l'O-GlcNAc globale n'a été observée dans le cerveau (p> 0,05), mais l'expression OGT et OGA (ARNm) était élevée chez les animaux C57 et BTBR (p <0,05). 

Le KD a des effets spécifiques sur les tissus sur O-GlcNAc. Bien que les niveaux d'O-GlcNAc jouent un rôle important dans le développement neurologique, les niveaux de cette modification dans le cerveau de souris juvénile étaient stables avec le KD malgré de grandes fluctuations de l'état énergétique. Cela suggère qu'il est peu probable que le KD exerce un avantage thérapeutique dans le modèle BTBR de TSA par les voies liées à O-GlcNAc. 

Biochim Biophys Acta. 2017 May 11. pii: S0925-4439(17)30150-3. doi: 10.1016/j.bbadis.2017.05.013.

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

Newell C¹, Johnsen VL², Yee NC³, Xu WJ⁴, Klein MS², Khan A⁵, Rho JM⁶, Shearer J⁷.

Author information

1

Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada; Department of Medical Science, University of Calgary Cumming School of Medicine, Calgary, AB, Canada. Electronic address: cnewell@ucalgary.ca.

2

Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.

3

Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, AB, Canada.

4

Department of Medical Science, University of Calgary Cumming School of Medicine, Calgary, AB, Canada.

5

Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, AB, Canada; Department of Medical Genetics and Pediatrics, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, AB, Canada.

6

Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, AB, Canada; Department of Paediatrics, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, Calgary, AB, Canada; Department of Clinical Neurosciences, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, Calgary, AB, Canada; Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, Calgary, AB, Canada.

7

Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada; Department of Medical Science, University of Calgary Cumming School of Medicine, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, AB, Canada.

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 BTBR^T+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.

Copyright © 2017. Published by Elsevier B.V.

PMID: 28502704

DOI: 10.1016/j.bbadis.2017.05.013