Actions of appetite regulating peptides on supraoptic nucleus (SON) oxytocin neurones

Abstract

Oxytocin has established roles in parturition and lactation, but can also be released in response to non-reproductive stimuli, such as hyperosmolarity and stress. As a majority of appetite regulating peptides activate the hypothalamo-pituitary-adrenal stress axis, and oxytocin is also a stress hormone in the rat, it was hypothesized that the oxytocin system in the neurohypophysial axis could be a target for appetite-regulating peptides of central and peripheral origin. The effects of central administration of neuropeptide Y (NPY; a central orexigenic peptide and a central and peripheral neurotransmitter co-released with noradrenaline; n=5 rats) and systemic administration of secretin (a peripheral gut peptide belonging to the family of brain-gut peptides; n=26) and leptin (a peripheral anorexigenic peptide from adipose tissue; n=23) on the electrical activity of SON oxytocin neurones in vivo were studied in urethane-anaesthetized female rats with extracellular recording. Effects were compared with the excitatory responses to cholecystokinin (CCK; a peripheral anorexigenic gut peptide; n=45). Influences of fasting and pregnancy and effects of these peptides on the activity of SON vasopressin neurones were also studied. Results: (1) All the central and peripheral appetite peptides tested increased the electrical activity of SON oxytocin neurones. (a) NPY: Basal firing rate of 3.5 ± 1.05 (mean ± s.e.m) spikes/s was increased by 1 ± 0.45 spikes/s 1min after NPY (basal vs 0-10min post-NPY: P=0.03, paired t-test; n=5). (b) Secretin: Basal rate of 4.1 ± 0.4 spikes/s was increased by 1.7 ± 0.2 spikes/s 2.5min after secretin (basal vs 0-10min post-secretin: P<0.001, paired t-test; n=26). (c) Leptin: Basal rate of 3.4 ± 0.4 spikes/s was increased by 0.4 ± 0.08 spikes/s 1.5min after leptin (basal vs 0-10min post-leptin: P=0.01, paired t-test; n=23). (d) CCK: Basal rate of 3.6 ± 0.3 spikes/s was increased by 1.1 ± 0.15 spikes/s 1min after CCK (basal vs 0-10min post- CCK: P<0.001, Wilcoxon signed rank test; n=45). (2) Secretin induced excitatory responses were greater than to other peptides (P<0.001, Kruskal-Wallis one-way ANOVA on ranks). (3) Secretin dose-dependently increased SON oxytocin neurone electrical activity and peripheral oxytocin release in anaesthetized rats. (4) Intracerebroventricular infusion and microdialysis studies with benoxathian (α1 adrenergic antagonist) revealed that secretininduced excitation of SON oxytocin and vasopressin neurones involves central excitatory noradrenergic pathways. (5) Fasting for 18h did not alter the excitation of SON oxytocin neurones induced by secretin, CCK and leptin. (6) The pathway leading to excitation of oxytocin neurones by CCK was not influenced by prior leptin administration. (7) SON oxytocin neurones were responsive to leptin during late pregnancy. (8) NPY-induced excitation of oxytocin neurones was intact in anaesthetised late pregnant rats, contrasting with attenuated oxytocin secretory responses observed previously in conscious rats. (9) Systemic NPY excited SON oxytocin neurones. (10) Systemic CCK administration either inhibited (77%) or did not affect (23%) SON vasopressin neurones, while leptin had no significant effect, and responses to secretin were predominantly excitatory (67%). Systemic NPY inhibited vasopressin neurones, but central NPY was ineffective. Conclusion: Appetite peptides target SON oxytocin neurones. Postprandially released secretin and leptin might, like CCK, induce peripheral oxytocin release, so as to regulate water and electrolyte homeostasis, which is inevitably disturbed during feeding. Any central release of oxytocin induced by these peptides, might regulate feeding behaviour and satiety. Oxytocin neurone excitation induced by NPY may be relevant during stress responses.