Exendin-4 Improves Long-Term Potentiation and Neuronal Dendritic Growth in High-Fat Diet Mice and Neurons Under Metabolic Imbalance Conditions

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes, has emerged as a significant issue worldwide. Metabolic syndrome can occur due to diverse factors such as genetic background, lifestyle changes, food intake, and aging. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies, such as synaptic dysfunction and memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells, and specific brain nuclei play multiple roles, including glucose metabolism, regulation of insulin sensitivity, inflammation control, synaptic plasticity improvement, and neuronal protection. Even though GLP-1 and GLP-1 receptor agonists (GLP-1RA) appear to have neuroprotective functions, the specific mechanisms of GLP-1 and GLP-1RA in brain function have remained unclear. Here, we investigated whether exendin-4 improves cognitive function and brain insulin resistance in metabolic imbalanced high-fat diet mice brain as a GLP-1RA, using electrophysiological experiments. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons under an in vitro metabolic imbalance condition, including neuronal structure improvement. This study provides significant findings on the effects of exendin-4 in synaptic plasticity, long-term potentiation (LTP), neuroinflammation, and neural structure. We suggest that GLP-1 may be vital to treating neuropathology caused by metabolic imbalance.