ArticleNature communications2017
Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers, 1 of them a synthesis that pooled it.
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Who cites it
131 citing papers in PubMed, 1 synthesis or guideline pooled it, 195 citations in OpenAlex.
- The effect of physical activity interventions on cognition function in patients with diabetes: A systematic review and meta-analysis.Diabetes/metabolism research and reviews · 2021Pooled it
- Biliverdin reductase A deficiency reveals sex- and brain region-specific vulnerability to high-fat diet feeding.Redox biology · 2026Article
- Palmitoylation calibrates mitochondrial transport of insulin across the endothelium in insulin resistance.bioRxiv : the preprint server for biology · 2026Article
- Light-activated insulin receptor modulates neuronal plasticity and cerebellar-driven behavior.iScience · 2026Article
- Palmitic acid-induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration.Neural regeneration research · 2026Article
- Posttranslational modifications of AMPA receptors in synaptic function and memory.Cellular and molecular life sciences : CMLS · 2026Review
- Diet, Metabolism and Synaptic Function: Integrating Evidence Across Models in Neurodegeneration Research.Biomedicines · 2026Review
- Glycogen Synthase Kinase-3β Mediates Suppression of Neurite Outgrowth Through Sonic Hedgehog Signalling in Palmitic Acid-Exposed Neuro2A Cells.Molecular neurobiology · 2026Article
- Lipid-induced S-palmitoylation of Insulin-Responsive Aminopeptidase (IRAP) drives the onset of insulin resistance in the heart.Cellular and molecular life sciences : CMLS · 2026Article
- Protein Acylation Modifications in Sleep Disorders: Mechanisms and Therapeutic Potential.Journal of molecular neuroscience : MN · 2026Review
- Insulin Resistance Surrogates and Cognitive Impairment in Parkinson's Disease: A Cross-Sectional Study with Interpretable Machine Learning.Biomedicines · 2026Article
- The promise of GLP-1 receptor agonists for neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- From Metabolism to Mind: The Cardio-Metabolic-Brain Axis and the Role of Insulin Resistance-A Review.Biomedicines · 2026Review
- Review
- Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.Frontiers in aging neuroscience · 2026Review
- One-month early time-restricted eating enhances cognition via white matter-cortical pathways in males with metabolic syndrome: evidence from TBSS and SBM analyses.Frontiers in nutrition · 2026Article
- Muscle-brain crosstalk in sarcopenia and cognitive impairment: endocrine signaling, metabolic regulation, and exercise modulation.Frontiers in endocrinology · 2026Review
- Bitter Compounds as Multifunctional Agents against Diabetes-associated Cognitive Dysfunction: Bridging Metabolic Regulation and Neuroprotection.Mini reviews in medicinal chemistry · 2026Review
- Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications.Chinese herbal medicines · 2026Review
- An Investigation of the Causal Link Between Palmoylation Genes and Epilepsy Utilising Multi-omics Mendelian Randomisation Analysis and Validation Through Single-Cell Evidence.Journal of molecular neuroscience : MN · 2025Article
71 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
High-fat diet (HFD) and metabolic diseases cause detrimental effects on hippocampal synaptic plasticity, learning, and memory through molecular mechanisms still poorly understood. Here, we demonstrate that HFD increases palmitic acid deposition in the hippocampus and induces hippocampal insulin resistance leading to FoxO3a-mediated overexpression of the palmitoyltransferase zDHHC3. The excess of palmitic acid along with higher zDHHC3 levels causes hyper-palmitoylation of AMPA glutamate receptor subunit GluA1, hindering its activity-dependent trafficking to the plasma membrane. Accordingly, AMPAR current amplitudes and, more importantly, their potentiation underlying synaptic plasticity were inhibited, as well as hippocampal-dependent memory. Hippocampus-specific silencing of Zdhhc3 and, interestingly enough, intranasal injection of the palmitoyltransferase inhibitor, 2-bromopalmitate, counteract GluA1 hyper-palmitoylation and restore synaptic plasticity and memory in HFD mice. Our data reveal a key role of FoxO3a/Zdhhc3/GluA1 axis in the HFD-dependent impairment of cognitive function and identify a novel mechanism underlying the cross talk between metabolic and cognitive disorders.
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