Effects of Central Insulin Resistance on Neuronal Functions and Metabolic Coupling between Neurons and Astrocytes

Abstract

Clinical evidence has shown the intimate relationship between insulin resistance and impaired cognitive performance in diabetic patients. However, the underlying mechanism remains unclear. The metabolic coupling between neurons and astrocytes is reported to be essential for neuronal development and memory formation. However, whether the metabolic coupling is affected under insulin resistant condition and its relationship with cognitive performance are not yet identified. By establishing the insulin resistant neuron-astrocyte coculture system, we discovered that insulin resistance impaired neuronal synaptic plasticity and accelerated cellular apoptosis. Impaired cognitive performance was observed in high-fat diet mice. More importantly, we identified the damaged metabolic coupling between neurons and astrocytes, evidenced by the reduced lactate transportation from astrocytes to neurons as well as decreased expressions of monocarboxylic transporters (MCTs) in vivo and in vitro. We also observed alterations in cellular glycolysis in both neurons and astrocytes at different time points under insulin resistance. The neuronal and astrocytic glycolysis were affected at the early phase (3h, 6h), then the astrocytic glycolysis increased along with the increase of lactate level in astrocytes. In neurons, the cellular glycolysis remained stable to produce efficient lactate for neuronal function maintenance. Thus, the impaired metabolic coupling between neurons and astrocytes as well as the significant glycolysis shifts in brain cells played an important role in the impairment of synaptic plasticity and cognitive decline, which shed lights on the treatment for diabetes-related cognitive decline in the near future. Funding: This work was supported by the grant (belonging to Guixia Wang) from the National Natural Science Fund of China (81670732) and the grant from the Jilin Province Development and Reform Commission (2013C036-4). Declaration of Interest: There is no conflict of interest. Ethical Approval: Experiments were performed in accordance with the guidelines for experimental animal use of Jilin University. The protocol applied in the study was approved by the ethics committee of the First Hospital of Jilin University.