Figure 8: Schematic illustration of the proposed model.

Alterations in glucose levels regulate AMPK activity in the ARC circuit. Inhibition by leptin of AMPK in presynaptic GABAergic axon terminals reduces GABA release to POMC cells. In contrast, leptin receptor activation on POMC neurons stimulates the JAK2–PI3K–PLC pathway, resulting in opening of TRPC channels and probably inositol 1,4,5-trisphosphate receptors as well. Increased Ca²⁺ concentrations trigger the release of melanocortin and glutamate from glutamatergic POMC neurons. Short-term exposure to a high-fat diet upregulates PI3K activity specifically in POMC neurons. Under these conditions, leptin no longer reduces GABA release from presynaptic GABAergic neurons. However, the JAK2–PI3K–PLC pathway by leptin in POMC neurons remains effectively transmitted, thereby enhancing GABAergic inhibitory tone to POMC neurons. This feedback inhibition of POMC neurons in animals on high-fat feeding may play a role in the regulation of overall energy balance.