Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release

Abstract

Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. Neuropeptide Y (NPY) is a 36-amino acid peptide of the pancreatic polypeptide family, with homology to pancreatic polypeptide (PP, Ϸ50%) and peptide YY (PYY, Ϸ70%) (1). NPY is one of the most abundant neuropeptides in the central and peripheral nervous system of many mammals, including humans (2). NPY immunoreactivity is present throughout the brain, particularly in the hypothalamus (2). Within the hypothalamus NPY is implicated in the activation of the hypothalamic pituitary adrenal (HPA) axis (3), the regulation of growth, and sexual function (4), and is the most potent stimulant of feeding yet reported (5, 6).Several NPY receptor subtypes have been identified and characterized by their ability to bind NPY, PYY, and PP fragments and analogues. The NPY Y1 receptor binds with high affinity full-length NPY or analogues, such as [Pro 34 ]NPY or [Leu 31 Pro 34 ]NPY (7). The Y1 receptor has a reduced affinity for C-terminal fragments such as NPY(2-36), NPY(3-36), and NPY(13-36) (8). This receptor has been cloned from the human (9) and rat (10) central nervous system and is expressed in the human neuroblastoma cell line, SK-N-MC (9). The Y2 receptor has a high affinity for C-terminal fragments such as NPY(13-36) and NPY(3-36) (8) but a low affinity for [Pro 34 ]NPY, and has been cloned from human hippocampus (11) and from the human neuroblastoma cell line, SMS-KAN (12). Human neuroblastoma cell lines are considered the de facto standards for the characterization of ligands for Y1 and Y2 receptors. PYY binds with high affinity to both the Y1 and Y2 receptor subtypes, whereas human and rat PP bind with very low affinities (9,11,13). A group of receptors with disparate pharmacological profiles have been labeled Y3 and are characterized by a low affinity for PYY in comparison to NPY (14-16). Hypotension, bradycardia, and inhibition of glutamate effects in response to unilateral injection of NPY into the nucleus tractus solitarius of the rat are associated with Y3 receptor activation in the central nervous system (17, 18). The Y4 receptor is characterized by a very high affinity for PP compared with NPY and NPY(13-36) (13, 19). The Y4 receptor has been cloned and its mRNA is expressed in the human brain, coronary artery, and ileum (19). An NPY receptor designated Y6 has been cloned from mouse (20), human, chimpanzee, gorilla, and rabbit (21) but is inactivated in primates by a frame-shift mutation. The Y6 receptor has a high affinity for NPY and PYY and a low affinity for human PP (20,21).NPY has been proposed to activate a hypothalamic ''feeding'' receptor (Y FEEDING ) distinct from previously cloned NPY receptors (22,23). This receptor was initially suggested to be Y1-like because [Pro 34 ]NPY mediates a pot...

Interactions between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis

“…It has been shown that only intact NPY can stimulate ACTH and cortisol release in dogs, whereas its C-terminal fragment, NPY (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), and the NPY analog, NPY (1-36)-OH, are ineffective (12). In contrast, Small et al (18), using different NPY analogs, have obtained results suggesting that the rat hypothalamic NPY receptor, which increased plasma ACTH concentrations, has a fragment activation profile unlike those of Y1-Y4 and Y6 receptors, and appears distinct from the NPY receptor controlling food intake. They also suggest that the activity of this receptor seems to be similar to that of the Y5 receptor.…”

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

“…Intracerebroventricular (ICV) administration of NPY stimulates food intake (Clark et al 1985;Levine and Morley 1984;Stanley and Leibowitz 1984), modulates cognition (Flood et al 1987;Redrobe et al 1999), inhibits neuronal excitability (Colmers and Bleakman 1994) and has anticonvulsant effects (Vezzani et al 1999). NPY modulates the secretion of various hypothalamic neuropeptides, stimulates the corticotrophic axis (Krysiak et al 1999;Small et al 1997) and has potent inhibitory effects on gonadotrophic and somatotrophic axes (Catzeflis et al 1993). In addition, NPY is thought to play a role in the pathophysiology of certain mood disorders and in the mechanism of action of antidepressant drugs (Heilig et al 1988;Caberlotto et al 1998 (Michel et al 1998).…”

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

“…After this period, rats were given a further week of daily handling to habituate them to all experimental procedures and minimize stress. A positive dipsogenic response to ICV injection of angiotensin II (ANG II; 150 ng/rat), as previously described (16,40,41), verified cannula placement. If an animal ate <10 g of food in a 24-h period or lost >10 g body wt over a 48-h period, it was considered unwell and excluded from the study.…”