Purinergic signaling by <scp>ATP</scp> induces exercise‐like effects and ameliorates insulin resistance in <scp>HT22</scp> 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.