Abstract
ObjectiveNeuropeptide 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. MethodsPatch 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. ResultsWe 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. ConclusionThus, 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.
Highlights
Neuropeptide Y (NPY) is a key peptide in the central regulation of energy homeostasis [1]
Regulation of the synaptic inputs of parvocellular neurons in the paraventricular nucleus (PVN) by NPY involves release of Ca2þ from the endoplasmic reticulum and activation of retrograde transmitter systems To understand the effects of NPY on the parvocellular neurons of the PVN, patch clamp electrophysiology combined with calcium imaging were performed
Endocannabinoid and the nitric oxide (NO) systems mediate different functions of NPY in the PVN in the regulation of energy homeostasis To determine the role of the two retrograde transmitter systems in mediating the various actions of NPY on energy balance within the PVN, we studied whether local administration of inhibitors of the endocannabinoid and NO systems influence the effects of NPY on food intake, energy expenditure, substrate utilization, and locomotor activity
Summary
Neuropeptide Y (NPY) is a key peptide in the central regulation of energy homeostasis [1]. Central administration of NPY markedly stimulates food intake and inhibits energy expenditure [2]. Synthesis of NPY and the second orexigenic peptide produced by these cells, Agouti related peptide (AgRP), are stimulated by fasting and inhibited by administration of leptin [1]. One of the main brain regions where NPY exerts its effects on food intake and energy expenditure is the hypothalamic paraventricular nucleus (PVN). Focal administration of NPY into the PVN markedly increases food intake [6] and carbohydrate utilization [7], decreases energy expenditure, the expression of uncoupling protein 1 in brown adipose tissue [8,9], and induces body weight gain [10]
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