Neuronal CCL2 responds to hyperglycaemia and contributes to anxiety disorders in the context of diabetes

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.