ArticleNature metabolism2025
Neuronal CCL2 responds to hyperglycaemia and contributes to anxiety disorders in the context of diabetes.
Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Aflatoxin B1 Induces Anxiety-related Neurotoxicity Through Brain-region-Specific EGFR/AKT Signaling: Evidence from Integrative Network Toxicology and Mendelian Randomization.Applied biochemistry and biotechnology · 2026Article
- Association of triglyceride-glucose index with anxiety in first-episode, drug-naïve major depressive disorder: role of subclinical hypothyroidism.European archives of psychiatry and clinical neuroscience · 2026Article
- Bidirectional association between immune-mediated diseases and major depressive disorder: evidence from cohort, genome-wide pleiotropic, and experimental studies.Molecular psychiatry · 2026Article
- Analysis of Anxiety and Depression Status and Risk Factors in Postmenopausal Women With Diabetes Mellitus Complicated by Hypothyroidism.Actas espanolas de psiquiatria · 2026Article
- ZBP1 Mediates Renal Tubular Injury in Diabetic Nephropathy Through RIPK3-mediated Necroptosis.Inflammation · 2026Article
- Integrated gut microbiota and metabolome analyses link anger to metabolic dysregulation in patients with type 2 diabetes mellitus.Frontiers in microbiology · 2026Article
- The impact of high-sugar diets on central nervous system disorders: mechanisms, pathogenesis, and dietary implication.Annals of medicine · 2025Review
- Anxiolytic Effects of Natural Products: Pathological Mechanisms, Molecular Targets, Therapeutic Prospects.Neuropsychiatric disease and treatment · 2025Review
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
Anxiety disorders are frequently observed in patients with diabetes and can be associated with several diabetes-related factors. Here we determine that hyperglycaemia is a major cause for the development of anxiety disorders through a C-C motif chemokine ligand 2 (CCL2)-dependent mechanism. By adopting complementary strategies, we demonstrate that neuron-specific (not peripheral) CCL2 mediates anxiety-like behaviours in streptozotocin-induced diabetic mice. Mechanistically, high glucose levels induce Tonicity-responsive enhancer-binding protein (TonEBP)-dependent CCL2 expression in neurons, leading to microglial activation in a paracrine manner. Similar phenotypes are also observed in high-fat diet-induced diabetic mice, independent of insulin signalling. Furthermore, we reveal that neuronal CCL2 in the medial prefrontal cortex and ventral hippocampus synergistically induces anxiety-like behaviours, indicating brain region-specific effects on diabetic mice. Finally, we confirm that the neuronal TonEBP-CCL2 axis and inflammatory pathways are both upregulated in patients with diabetes. Conclusively, neuronal CCL2 is specifically increased by hyperglycaemia and contributes to anxiety disorders, providing additional insights into the link between diabetes and mental health disorders.
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Registered trials
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