High fat diet leads to aberrant protein O‐GlcNAcylation and to the development of Alzheimer disease signatures in mice

Abstract

AbstractBackgroundHigh fat diet (HFD) is the most commonly used experimental model of obesity and insulin resistance, resembling the hallmarks of humans metabolic syndromes. It causes detrimental effects on brain function, but the molecular mechanisms involved are still poorly understood. Recent studies show that HFD may lead to the reduction of glucose uptake, which represent an early step in neuronal damage. In this regard, Alzheimer’s disease (AD) was recently proposed to be a form of CD caused by metabolic dys‐homeostasis. Intriguingly, during AD glucose hypometabolism precedes the appearance of clinical symptoms leading to the downregulation of O‐GlcNAcylation, a reversible glucose‐dependent protein PTM, which competes with phosphorylation for Ser or Thr residues. The enzymes (OGT and OGA) regulating the O‐GlcNAcylation cycle rely on brain nutrients through the hexosamine biosynthesis pathway for substrate availability. Recent studies from our lab observed the reduction of O‐GlcNAcylation in the hippocampus of insulin resistant 3xTG‐AD mice supporting a role for this PTMs in the development of CD.MethodWe employed C57 mice fed for 6 weeks with HFD (60% calories from fat) compared with C57 fed with standard diet. Further, we subjected mouse astrocyte to insulin + palmitic acid (IPA) treatment for 24h. The experimental procedures encompassed the analysis of: total and protein specific O‐GlcNAcylation and phosphorylation on Ser and Thr residues, OGT and OGA levels and activity, Tau and APP PTMs and the alteration of metabolic parameters.ResultWe demonstrate that HFD mice show the reduction of protein O‐GlcNAcylation in the hippocampus but not in the liver. Such reduction lead to unbalanced O‐GlcNAcylation/phosphorylation ratio of total proteins and of tau and APP, suggesting its involvement in the development of pathological tau and Aβ. A reduction of OGT protein levels is reported in hippocampal cells supporting a role for this enzyme as metabolic sensor. Similarly, astrocytes treated with IPA show insulin resistance coupled with reduced O‐GlcNAcylation and the progression of AD markers. Intriguingly, altered O‐GlcNAcylation seems to be associated also with mitochondrial defects.ConclusionOur data support a key role for aberrant O‐GlcNAcylation in promoting the development of AD markers during diet‐driven brain insulin resistance and glucose hypo metabolism.