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

Abstract Background 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. Results 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. Conclusion 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.