Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

The activation of the hypothalamic-pituitary-adrenal (HPA) axis is essential for metabolic adaptation in response to fasting. However, the neurocircuitry connecting changes in the peripheral energy stores to the activity of hypothalamic paraventricular corticotrophin-releasing factor (CRF^PVN) neurons, the master controller of the HPA axis activity, is not completely understood. Our main goal was to determine if hypothalamic arcuate nucleus (ARC) POMC and AgRP neurons can communicate fasting-induced changes in peripheral energy stores, associated to a fall in plasma leptin levels, to CRF^PVN neurons to modulate the HPA axis activity in mice.

We observed increased plasma corticosterone levels associate with increased CRF^PVN mRNA expression and increased CRF^PVN neuronal activity in 36 h fasted mice. These responses were associated with a fall in plasma leptin levels and changes in the mRNA expression of Agrp and Pomc in the ARC. Fasting-induced decrease in plasma leptin partially modulated these responses through a change in the activity of ARC neurons. The chemogenetic activation of POMC^ARC by DREADDs did not affect fasting-induced activation of the HPA axis. DREADDs inhibition of AgRP^ARC neurons reduced the content of CRF^PVN and increased its accumulation in the median eminence but had no effect on corticosterone secretion induced by fasting.

Our data indicate that AgRP^ARC neurons are part of the neurocircuitry involved in the coupling of PVN^CRF activity to changes in peripheral energy stores induced by prolonged fasting.