Melanocortin-4 receptor activation promotes insulin-stimulated mTOR signaling

The melanocortin signaling system is integral in regulating energy homeostasis. The melanocortin-4 receptor (MC4R) activates several signaling pathways in performance of this function. The effect of MC4R on insulin-stimulated mammalian target of rapamycin (mTOR), a cellular energy sensor, signaling was investigated. The GT1-1 cell line which expresses MC4R expression was utilized. mTOR signaling was measured by Western blotting analysis using Phospho-mTOR (Ser2448) antibody. NDP-MSH dose-dependently enhanced insulin-stimulated mTOR phosphorylation. The MC4R antagonist SHU9119 blocked this effect, demonstrating specificity. The protein kinase A – cyclic AMP pathway and the MAP kinase pathway were not involved in NDP-MSH actions on insulin-stimulated mTOR phosphorylation. In contrast, the AMP-activated protein kinase agonist, AICAR, attenuated this effect. MC4R activation potentiates insulin-stimulated mTOR signaling via the AMPK pathway.

Research highlights
• Melanocortin receptor 4 agonist NDP-MSH potentiates insulin-stimulated mTOR phosphorylation in GT1-1 cells.
• cAMP pathway inhibitor Rp-cAMP and MAP kinase pathway inhibitor PD98059 are not involved in NDP-MSH actions on insulin-stimulated mTOR phosphorylation.
• AMP-activated protein kinase agonist AICAR attenuates the effect of NDP-MSH on insulin-stimulated mTOR phosphorylation.