Endocannabinoid and nitric oxide systems of the hypothalamic paraventricular nucleus mediate effects of NPY on energy expenditure

Zoltán Péterfi, Imre Farkas, Raphael G.P. Denis, Erzsébet Farkas, Motokazu Uchigashima, Tamás Füzesi, Masahiko Watanabe, Ronald M. Lechan, Zsolt Liposits, Serge Luquet, Csaba Fekete


Neuropeptide Y (NPY) is a key peptide in the central regulation of energy homeostasis. One of the main brain regions where NPY exerts its effects on food intake and energy expenditure is the hypothalamic paraventricular nucleus (PVN). Péterfi, Farkas, Denis, Farkas, et al. describe that NPY seems to exert rapid action on parvocellular PVN neurons by gating both inhibitory and excitatory inputs to these neurons via activation of endocannabinoid and nitric oxide retrograde signaling systems.

Objective: Neuropeptide Y (NPY) is one of the most potent orexigenic peptides. The hypothalamic paraventricular nucleus (PVN) is a major locus where NPY exerts its effects on energy homeostasis. We investigated how NPY exerts its effect within the PVN.

Methods: Patch clamp electrophysiology and Ca2+ imaging were used to understand the involvement of Ca2+ signaling and retrograde transmitter systems in the mediation of NPY induced effects in the PVN. Immuno-electron microscopy were performed to elucidate the subcellular localization of the elements of nitric oxide (NO) system in the parvocellular PVN. In vivo metabolic profiling was performed to understand the role of the endocannabinoid and NO systems of the PVN in the mediation of NPY induced changes of energy homeostasis.

Results: We demonstrated that NPY inhibits synaptic inputs of parvocellular neurons in the PVN by activating endocannabinoid and NO retrograde transmitter systems via mobilization of Ca2+ from the endoplasmic reticulum, suggesting that NPY gates the synaptic inputs of parvocellular neurons in the PVN to prevent the influence of non-feeding-related inputs. While intraPVN administered NPY regulates food intake and locomotor activity via NO signaling, the endocannabinoid system of the PVN selectively mediates NPY-induced decrease in energy expenditure.

Conclusions: Thus, within the PVN, NPY stimulates the release of endocannabinoids and NO via Ca2+-influx from the endoplasmic reticulum. Both transmitter systems appear to have unique roles in the mediation of the NPY-induced regulation of energy homeostasis, suggesting that NPY regulates food intake, energy expenditure, and locomotor activity through different neuronal networks of this nucleus.