Y2 Receptor-Selective Agonist Delays the Estrogen-Induced Luteinizing Hormone Surge in Ovariectomized Ewes, but Y1-Receptor-Selective Agonist Stimulates Voluntary Food Intake

Abstract

Neuropeptide Y (NPY) plays a major role in the regulation of food intake, regulation of homeostasis, and neuroendocrine function. We have previously shown that third ventricular infusion of this peptide delays the estradiol benzoate-induced surge in LH secretion in ovariectomized ewes. To determine the receptor subtype that transmits this effect, we have now used the same model to infuse a Y1 receptor agonist [NPY Leu31 Pro34], a Y2 receptor agonist (PYY3-36), and a Y4 receptor agonist (pancreatic polypeptide). We monitored the surges in animals given these agonists or artificial cerebrospinal fluid by measuring plasma LH levels, and we also measured daily voluntary food intake (VFI). A low (7 microg/h) dose of Y2 agonist delayed the surge but did not affect VFI, whereas a higher dose (14 microg/h) stimulated VFI. A dose of 18 microg/h of the Y1 agonist did not affect surge generation but also stimulated VFI. A dose of 24 microg/h of Y4 agonist affected neither surge generation nor VFI. These specificities are different from those reported for the rat and human (in which a Y2 agonist causes reduction in VFI). We conclude that, in sheep, the negative regulation of the reproductive axis by NPY and Y-receptor agonists is effected via the Y2 receptors, whereas the orexigenic effects are most likely effected via the Y1 receptors.

Gonadotropin-Inhibitory Hormone Is a Hypothalamic Peptide That Provides a Molecular Switch between Reproduction and Feeding

“…In this sense, we propose that GnIH may function as a molecular switch, between the two functions. This is consistent with the actions of a number of other peptides, which have opposing actions on reproduction and feeding, including NPY [40] and melanocortins [41], amongst others.…”

Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

“…Although NPY is a negative regulator of the reproductive axis in the ewe [9], the gene expression data and peptide data presented herein suggest that the GnRH/LH response to leptin treatment in lean hypogonadotropic animals is not explained by a reduction in the level of this peptide.…”

“…Most of the so-called ‘appetite-regulating peptides’ also regulate reproductive function, acting within the brain [6] to regulate gonadotropin-releasing hormone (GnRH) secretion [7]. Neuropeptide Y (NPY), agouti-related peptide (AgRP), and melanocortins are examples of peptides with such dual functions [8,9,10,11]. …”

Progesterone-Receptive Dopaminergic and Neuropeptide Y Neurons Project from the Arcuate Nucleus to Gonadotropin-Releasing Hormone-Rich Regions of the Ovine Preoptic Area

“…However, as NPY terminals are known to synapse on GnRH perikarya in the sheep [22, 23, 33, 51], it is reasonable to speculate that GnRH neurons may be receptive for NPY. Several subtypes of NPY receptors, including NPY-Y 1 , NPY-Y 2 and/or NPY-Y 5 , have been linked with a modulation of GnRH secretion in rats [60,61,62], and, more recently in sheep [63]. In rats, the coexistence of GnRH and NPY-Y 5 immunoreactivity was also demonstrated at the level of the soma [62], but NPY-Y 1 and NPY-Y 2 receptors appeared to be involved in the control of GnRH secretion at the level of the median eminence [60, 61].…”

“…In rats, the coexistence of GnRH and NPY-Y 5 immunoreactivity was also demonstrated at the level of the soma [62], but NPY-Y 1 and NPY-Y 2 receptors appeared to be involved in the control of GnRH secretion at the level of the median eminence [60, 61]. In sheep, recent findings using specific receptor subtype agonists suggested that NPY-Y 2 receptors have probably a larger influence on GnRH secretion than NPY-Y 1 , which may be involved in food intake [51, 63]. We are currently determining if GnRH neurons express NPY receptors in the ovine brain.…”