Proopiomelanocortin (POMC) neurons of arcuate nucleus in the hypothalamus has well known as first order neuron to regulate satiety and energy metabolism by responding energy state dependent hormonal signals like leptin from peripheral organs. These hormonal signals regulate not only neural activity of POMC neurons but also their synaptic rewiring with other neurons in the central nervous system. However, detail mechanism how synaptic transmission changing was unknown.
In this study, we showed excitatory input onto POMC neurons are regulated via re-composition of AMPA type glutamate receptor subtype expression in the postsynaptic site dependent on energy state. Under fasted condition as negative energy state, amplitude of EPSC was decreased and I-V relationship of AMPAR showed dominant expression of GluR2 contain, calcium impermeable (CI) AMPARs compared with ad lib fed state. On the other hand, short-term (10 days) high fat diet feeding as positive energy state promote GluR2 lacking, calcium permeable (CP) AMPAR expression. Removing extracellular calcium or treatment of CP-AMPAR blocker decreased amplitude of EPSC onto POMC neruons under fed condition but not fasted condition. Interestingly, amplitude of EPSC without extracellular calcium was same between fed and fasted state, indicate the deference of synaptic transmission between these condition due to constitution of AMPAR subtype but not amount of receptor expression.
Leptin application to the fasted mice eliminated liner I-V relation of AMPARs. Rapamycin, a blocker of mTOR witch is downstream target of leptin, treatment to the fed mice disappear AMPAR rectrification. These data indicated re-composition of AMPAR at postsynapse of POMC neurons triggered by leptin-mTOR signaling.
In summary, negative energy, low leptin condition promoting GluR2 contained, CI-AMPAR expression suppress activity of POMC neurons whereas positive energy, high leptin condition promoting GluR2 lacking, CP-AMPAR expression facilitate POMC neuronal activity to promote satiety.