Atomoxetine and Fluoxetine Activate AMPK-ACC-CPT1 Pathway in Human SH-SY5Y and U-87 MG Cells

Objective Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus.Methods Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase (3 (CaMKK(3) using immunoblotting and CPT1 enzymatic activity measures.Results Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30-60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKK(3 inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKK(3 phosphorylation.Conclusion These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKK(3 in human SH-SY5Y and U-87 MG cells. Psychiatry Investig 2023;20(3):212-219