Neuropeptide Y (human, rat)

Neuropeptide Y-(2-36) has been reported by several research groups to be a more potent orexigenic agent than intact neuropeptide Y. Therefore, it has been proposed that a novel 'Y1 variant' may modulate ingestive behavior. To define the receptor subtype involved in neuropeptide Y-stimulated feeding behavior, we evaluated the binding properties of neuropeptide Y-(2-36) and [125I]neuropeptide Y-(2-36) in established neuropeptide Y1 and Y2 containing cell lines and tissues. Neuropeptide Y-(2-36) displaced [125I]peptide YY binding to SK-N-MC cells (neuropeptide Y Y1 receptors) with a Ki of 3.69 nmol and SK-N-BE(2) cells (neuropeptide Y Y2 receptors) with a Ki of 3.08 nmol. Neuropeptide Y-(2-36) also displaced [125I]peptide YY binding to rat cerebral cortex, hippocampus and olfactory bulb with similar affinities. To examine the brain distribution of [125I]peptide YY, [125I]neuropeptide Y and [125I]neuropeptide Y-(2-36), adjacent sections were labeled and the binding sites detected by autoradiography. A similar distribution of binding was observed for each radioligand in all regions examined. Therefore, neuropeptide Y-(2-36) binds non-selectively to neuropeptide Y Y1 and neuropeptide Y Y2 receptors, but with lower affinity than neuropeptide Y and peptide YY. The increased potency and selectivity seen with neuropeptide Y-(2-36) in feeding studies cannot be explained on the basis of a unique in vitro pharmacology.

Purpose of review:I review recent knowledge on the interference of neuropeptide Y with energy balance and cardiovascular and renal disease and on the central regulation of bone mass.Recent findings:Although neuropeptide Y is mainly seen as a vasoconstrictor, rats overexpressing the neuropeptide Y gene show reduced blood pressure and longer life span in comparison with control rats. Due to its strong mitogenic effects on vascular smooth muscle cells, neuropeptide Y induces occlusive lesions in a rat model of atherosclerosis induced by balloon angioplasty. The involvement of neuropeptide Y in experimental atherosclerosis is complex and may include also favourable, compensatory, mechanisms because, at physiological concentrations, it also activates a potent neoangiogenic response to ischemia. Subjects with a common genotype in the neuropeptide Y gene, which underlies increased intracellular neuropeptide Y storage, display slightly raised blood pressure, high serum cholesterol and increased carotid intima media thickness. In patients with end-stage renal disease high neuropeptide Y in plasma has been associated consistently with concentric left-ventricular hypertrophy and cardiovascular mortality. Finally, recent studies have shown that neuropeptide Y constitutes an important central regulator of bone mass and that it may be involved in inflammation and immune regulation.Summary:Evidence has accrued in experimental animals that altered neuropeptide Y is involved in obesity and the attendant metabolic complications. Recent data also suggest that this peptide may play a role in atherosclerosis and related cardiovascular complications.

Increased levels of neuropeptide Y correlate with severity of left ventricular hypertrophy in vivo. At cardiomyocyte level, hypertrophy is characterised by increased mass and altered phenotype. The aims were to determine the contributions of increased synthesis and reduced degradation of protein to neuropeptide Y-mediated increase in mass, assess effects on gene expression, and characterise neuropeptide Y Y receptor subtype involvement. Neuropeptide Y (10 nM) increased protein mass of adult rat ventricular cardiomyocytes maintained in culture (24 h) (16%>basal) and de novo protein synthesis (incorporation of [(14)C]phenylalanine) (18%>basal). Neuropeptide Y (100 nM) prevented degradation of existing protein at 8 h. Actinomycin D (5 microM) attenuated increases in protein mass to neuropeptide Y (< or = 1 nM) but not to neuropeptide Y (10 nM). [Leu(31), Pro(34)]neuropeptide Y (10 nM), an agonist at neuropeptide Y Y(1) receptors, increased protein mass (25%>basal) but did not stimulate protein synthesis. Neuropeptide Y-(3-36) (10 nM), an agonist at neuropeptide Y Y(2) receptors, increased protein mass (29%>basal) and increased protein synthesis (13%>basal), respectively. Actinomycin D (5 microM) abolished the increase in protein mass elicited by neuropeptide Y-(3-36) but not that by [Leu(31), Pro(34)]neuropeptide Y. BIBP3226 [(R)-N2-(diphenylacetyl)-N-(4-hydroxyphenylmethyl)-D-arginine amide] (1 microM), a neuropeptide Y Y(1) receptor subtype-selective antagonist, and T(4) [neuropeptide Y-(33-36)](4), a neuropeptide Y Y(2) receptor subtype-selective antagonist, attenuated the increase in protein mass to 100 nM neuropeptide Y by 68% and 59%, respectively. Neuropeptide Y increased expression of the constitutive gene, myosin light chain-2 (MLC-2), maximally at 12 h (4.7-fold>basal) but did not induce (t< or = 36 h) expression of foetal genes (atrial natriuretic peptide (ANP), skeletal-alpha-actin and myosin heavy chain-beta). This increase was attenuated by 86% and 51%, respectively, by BIBP3226 (1 microM) and T(4) [neuropeptide Y-(33-36)](4) (100 nM). [Leu(31), Pro(34)]neuropeptide Y (100 nM) (2.4-fold>basal) and peptide YY-(3-36) (100 nM) (2.3 fold>basal) increased expression of MLC-2 mRNA at 12 h. In conclusion, initiation of cardiomyocyte hypertrophy by neuropeptide Y requires activation of both neuropeptide Y Y(1) and neuropeptide Y Y(2) receptors and is associated with enhanced synthesis and attenuated degradation of protein together with increased expression of constitutive genes but not reinduction of foetal genes.