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 (CRFPVN) 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 CRFPVN neurons to modulate the HPA axis activity in mice. Results We observed increased plasma corticosterone levels associate with increased CRFPVN mRNA expression and increased CRFPVN 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 POMCARC by DREADDs did not affect fasting-induced activation of the HPA axis. DREADDs inhibition of AgRPARC neurons reduced the content of CRFPVN and increased its accumulation in the median eminence but had no effect on corticosterone secretion induced by fasting. Conclusion Our data indicate that AgRPARC neurons are part of the neurocircuitry involved in the coupling of PVNCRF activity to changes in peripheral energy stores induced by prolonged fasting.

A subpopulation of agouti-related peptide neurons exciting corticotropin-releasing hormone axon terminals in median eminence led to hypothalamic-pituitary-adrenal axis activation in response to food restriction

“…Similarly, serum corticosterone levels were increased two-fold in CNO-treated group compared with the FR group ( Supplementary Figure 3D ). Our findings are consistent with the recent study ( Fernandes et al, 2022 ) where they compared both a 24 h and a 36 h fasting protocol. 36 h fasting elevated the mRNA expression of CRH in the PVN and AgRP in the ARC like our CNO administration, whereas 24 h fasting increased AgRP mRNA in ARC but not CRH mRNA in PVN like our FR protocol.…”

“…These results indicate that this population of AgRP neurons directly projecting to the ME could contribute to modulation of CRH release from CRH neuronal axon terminals in response to FR ( Figure 6B ). This hypothesis has been supported by the very recent finding that inhibition of AgRP neurons in ARC in fasted animals increases CRH accumulation in the ME, indicating a reduction of release ( Fernandes et al, 2022 ).…”

Malocclusion impairs cognitive behavior via AgRP signaling in adolescent mice

“…The anorexigenic effect of Ucn2 may have contributed to the observed lack of change in food intake in the Malocclusion/powder group despite the increase in levels of the orexigenic peptide AgRP. Although AgRP neurons in the hypothalamus contribute to CRF activity in a fasted state ( Fernandes et al, 2022 ), the interaction between AgRP and Ucn2 has not yet been reported. The cognitive impairment in NOR test correlated with mRNA expression of AgRP, not Ucn2, in the present study.…”

Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits

“…Specifically, we show that AgRP neuron stimulation attenuates multiple measures of inflammation following paw injections of noxious stimuli. Previous studies have shown that AgRP neuron activity can also influence physiological measures such as metabolism, 36 glucose homeostasis, 48 , 49 adaptive immunity, 13 activation of the HPA axis, 50 , 51 and autonomic nerve activity. 52 These widespread effects that result from AgRP neuron activity highlight the pivotal role of these neurons in influencing both physiology and behavior.…”