High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

Abstract

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

A nexus of lipid and O-Glcnac metabolism in physiology and disease

“…In cells that cannot alternately utilize fatty acids as a fuel source, this would come with considerable energetic costs, especially in electrically active neurons. To that point, neural hypo- O -GlcNAcylation was dependent on the low energy sensor AMPK, both in this model ( 12 ) and in glucose-deprived neuroblastoma cells ( 37 ). In addition to preserving glycolytic substrate, reducing neural O -GlcNAcylation may stimulate LD growth as a method to sequester toxic lipid excess.…”

“…Both high fat-diet (HFD) and genetic obesity have been corelated to increased O- GlcNAcylation in multiple tissues, with some notable exceptions. Based on models of varying dietary fat (40-65%) and duration (1-5 months), elevated O- GlcNAcylation was observed in mouse liver ( 11 , 12 ), aorta ( 13 ), retina ( 14 ), kidney ( 15 ), white adipose tissue ( 16 ), intestine ( 17 ) and skeletal muscle ( 18 ) and in the rat heart ( 19 ) and cerebral arteries ( 20 ). A specific increase in nuclear O-GlcNAcylation was noted in the heart and liver but not kidneys of HFD rats ( 21 ).…”

“…Additionally, two mouse models of non-HFD obesity (db/db and ob/ob) showed higher kidney and liver O- GlcNAcylation, respectively ( 15 , 23 ). By contrast, hippocampal O- GlcNAcylation was reduced by ~30% in 6 week (wk) HFD mice compared to normal chow controls ( 12 ). This was similar to findings in male human islets in which obesity (BMI≥30) was correlated to hypo -O- GlcNAcylation compared to lean controls (BMI ≤ 25) ( 24 ).…”

“…At the same time, glucose-driven O- GlcNAcylation is neuroprotective against multiple cognitive disorders [for review ( 36 )]. Lipotoxic insulin resistance in the brain disrupts glucose metabolism and has been proposed as a causal link between obesity and Alzheimer’s disease ( 12 ). Therefore, the rationale and/or mechanisms for lipid sensing and lipid modulation of protein O -GlcNAcylation may be different in these cells compared to others.…”

Editorial: Brain Insulin Resistance in Neurodevelopmental and Neurodegenerative Disorders: Mind the Gap!

“…Among the intracellular processes dependent on the rate of glucose uptake, that are altered under insulin resistance conditions, O-GlcNAcylation post-translational modifications emerged as a key process regulating protein functions (Moll et al, 2020 ; Zuliani et al, 2021 ). Ansari and Emerald discuss the reciprocal interaction between insulin signaling and O-GlcNAcylation process in the brain, highlighting that increased O-GlcNAcylation of active sites of proteins of insulin signaling may promote the development of brain insulin resistance.…”