Purinergic signaling by ATP induces exercise-like effects and ameliorates insulin resistance in HT22 mouse hippocampal cells.

Neuronal insulin signaling is essential for regulating glucose metabolism and cognitive functions in the brain. Disruptions cause neuronal insulin resistance, potentially causing type 2 diabetes (T2D) and Alzheimer's disease (AD). Therefore, we investigated alternative pathways that maintain glucose homeostasis beyond traditional insulin signaling. Exercise positively impacts both body and brain well-being. However, brain exercise signaling remains unclear, and in vitro studies are limited. Here, we investigated the effects of extracellular ATP on HT22 mouse hippocampal neurons. ATP-mediated purinergic signaling elevated markers upregulated by exercise, increased glucose uptake, and activation of insulin signaling molecules. Under insulin resistance, ATP outperformed insulin, acting as an exercise-like bypass mechanism. This study provides new insights into purinergic receptors, ATP, and their potential to combat T2D and AD.