Neuropeptide Y
Neuropeptide Y, is a 36 amino acid peptide, synthesised in the arcuate nucleus and released in the paraventricular nucleus of the hypothalamus. Neuropeptide Ybelongs to the pancreatic polypeptide fold family which also includes Peptide YY and Pancreatic Polypeptide. Neuropeptide Y is the most potent stimulator of feeding known to man. Eur J Pharmacol. 2002 Apr 12;440(2-3):173-87 perhaps challenged only by PYY. J Pharmacol Exp Ther. 1994 Feb;268(2):1010-4 NPY promotes net energy gain by increasing food intake, while decreasing energy expenditure. NPY exerts peripheral effects with stimulation of glucocorticoid and insulin secretion favoring further deposition of triglycerides in white adipose tissue.
NPY and the Hypothalamic nuclei
NPY producing neurons are present in hypothalamic (ARC and DMN) and extra-hypothalamic (brainstem) sites. NPY neurons in the brainstem innervatehypothalamic sites including ARC, VMN, DMN, and PMN. Thus there is a dual contribution to the NPY present in the hypothalamus namely local production and contribution from brainstem neurons. Analysis of c-fos activation by NPY administration demonstrates that the PVN and DMN are sites closely associated with NPY-induced feeding. Brain Res. 1995 Nov 6;698(1-2):227-31 NPY producing neurons also synapse in the ARC with neurons producing orexigenic signals as POMC and Galanin. Endocrinology. 1996 Jul;137(7):3069-78. |
NPY : physiological variations
Enhanced NPY release in the PVN was temporally correlated with food consumption in rats on a scheduled feeding regimen. The NPY release in these rats rose just before onset of feeding with progressive decrease with food consumption. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10931-5 Fasting increases NPY release in the PVN. Endocrinology. 1992 Aug;131(2):684-8. Prolongation of fasting resulted in hypersecretion of NPY suggesting the role of NPY in sustaining appetite. CSF levels of NPY seem to negatively correlate with body weight. Neuropsychobiology. 1988;19(3):121-4. Genetically obese rodents (ob/ob mice Endocrinology. 1993 May;132(5):1939-44 , db/db mice, fa/fa rats Brain Res. 1995 Sep 4;690(2):185-8. and cp/cp corpulent mice Peptides. 1995;16(4):757-71. ) show increased pre-pro-NPY mRNA in the ARC as well as increased NPY levels in PVN. Leptin deficiency in the ob/ob mice results in increased NPY-ergic signalling, while a defective leptin signal transduction due to a point mutation in the leptin receptor is the cause in db/db mice. Leptin resistance is thought to cause the increased NPY activity in Zucker (fa/fa) rats. Biochem Biophys Res Commun. 1995 Apr 26;209(3):944-52 NPY expression is also increased in diabetic rats. Endocrinology. 1992 Dec;131(6):2979-85. |
NPY: effects of administration
Acute intra-cerebroventricular administration of NPY results in a strong feeding stimulus in rodents, Peptides. 1986 Nov-Dec;7(6):1189-92. while longer term administration results in decreased thermogenesis and obesity. NPY administration into the third ventricle (paraventricular region of the hypothalamus) or the fourth ventricle (peri-brainstem areas) as well as the PFH (perifornical hypothalamus) Brain Res Bull. 1985 Jun;14(6):521-4. and POA results in stimulation of feeding. Brain Res. 1993 Feb 26;604(1-2):304-17. NPY administration centrally stimulates feeding in satiated rats. NPY also enhances ongoing feeding.Endocrinology. 1985 Dec;117(6):2435-42. The stimulation of feeding is dose-dependent, although at higher doses feeding stimulation was less marked (bell shaped curve). Regul Pept. 1987 Jan;17(1):31-9. Overall, NPY-induced feeding closely simulates the normal physiological feeding pattern in rodents. NPY promotes net energy gain by increasing food intake, decreasing energy expenditure, and exerting effects in peripheral tissues, including stimulation of glucocorticoid and insulin secretion that favour deposition of triglycerides in white adipose tissue. |
NPY receptors
Six different receptors (Y1-Y6) have been described. Y1 and Y5 receptors mediate the effect of Neuropeptide Y on food intake. Mice lacking Y5 receptor feed normally with normal responses to exogenous NPY but demonstrate late onset of weight gain. Nat Med. 1998 Jun;4(6):718-21. Fasting increases NPY Y1 mRNA expression in the hypothalamus. Regul Pept. 1998 Sep 25;75-76:391-5. Pre-treatment with NPY Y1 receptor antagonist attenuates NPY induced c-fos activation in the PVN as well as NPY-induced feeding. Mutant mice deficient in NPY Y1 receptor show mild reduction in daily food intake as well as NPY- induced feeding, but a marked reduction in fasting induced re-feeding Nat Med. 1998 Jun;4(6):722-6 with a late increase in bodyweight! Thus NPY is not crucial to maintain food intake and weight as shown by NPY knock out mice as well as Y1 and Y5 knock out mice maintaining "normal" feeding behaviour and body weight. Up regulation of Y1 receptors occurs in NPY deficient rats along with an up-regulation of Galanin resulting in compensatory responses in NPY deficient rats. The endocannabinoid system has also been suggested to contribute to the compensatory response in NPY knock out rats, as CB1 receptor (cannabinoid receptor) antagonists have been shown to suppress food intake in these rats to a similar extent as in control rats. Nature. 2001 Apr 12;410(6830):822-5. Neuropeptide Y receptor antagonists, particularly neuropeptide Y Y(1) receptor antagonists, may be useful anti-obesity agents. On the other hand, patients with Alzheimer's disease who often tend to have weight loss Int Psychogeriatr. 1992 Summer;4(1):103-18. have been shown to have low levels of NPY in the CSF, J Comp Neurol. 1985 Aug 22;238(4):390-400. and hence NPY or PYY in supraphysiological doses may be useful in stimulating appetite in these patients by producing stimulation of NPY receptors. |
NPY regulators
Insulin, Leptin, gonadal and adrenal steroids as well as cytokines can modulate the NPY system. Insulin has been suggested to have anorexic effects centrally, effects that are probably mediated through insulin receptors expressed in the medio-basal hypothalamus. Central infusion of insulin decreases the fasting induced increase in NPY gene expression. Endocr Rev. 1992 Aug;13(3):387-414 Lack of insulin receptor immunoreactivity on NPY neurons in the ARC makes it likely that the attenuation of NPY levels by insulin might be mediated by indirect mechanisms. Rats made diabetic (insulin deficient) by streptozotocin show increased NPY gene expression and NPY levels in PVN, Endocrinology. 1992 Dec;131(6):2979-85. associated with increased feeding. Insulin replacement therapy decreases both the NPY levels in the PVN as well as the hyperphagia. Brain Res. 1997 May 2;755(2):339-42. Postprandial insulin rise may thus contribute to satiety along with leptin (see below) through reduction of NPY release in the PVN.Endocrinology. 1995 Dec;136(12):5718-24 Leptin deficiency (ob/ob mice), Leptin resistance or leptin ineffectiveness due to leptin receptor mutations (fa/fa and db/db rats) results in increased NPY expression in the arcuate nucleus suggesting that leptin is normally a regulator of NPY. Leptin which induces satiety and weight loss via decreased food intake and increased thermogenesis produces a decrease in arcuate NPY mRNA when injected into leptin deficient mice. Diabetes. 1996 Apr;45(4):531-5. |
NPY system is also influenced by the HPA axis (hypothalamo-pituitary-adrenal) , although whether a physiological regulatory influence happens is still not clear. NPY neurons in the ARC have high density of glucocorticoid receptors. Neurosci Lett. 1988 Dec 19;95(1-3):13-8. NPY producing neurons are synaptically linked with CRH neurons in the PVN. Histochemistry. 1988;88(3-6):227-34. Microinjection of NPY into the PVN increases pituitary ACTH with increased cortisol secretion. Brain Res. 1987 Aug 4;417(1):33-8. Adrenalectomy did not produce significant changes Brain Res. 1994 Dec 5;665(2):201-12. or produced a slight decrease Brain Res Bull. 1990 Nov;25(5):711-5. in hypothalamic NPY levels or gene expression in the ARC; nor did adrenalectomy produce any significant decrease in food intake, which might be explained by the depressed metabolic responses in adrenalectomised animals. This may demonstrate the lack of coupling of the diurnal HPA axis rhythm to NPY induced feeding. But, Glucocorticoid replacement in adrenalectomised rats increases NPY gene expression in the ARC with increased food intake and weight gain. J Neuroendocrinol. 1994 Apr;6(2):153-9. Circulating Glucocorticoid levels increase during starvation or fasting and this might contribute to the increased hypothalamic NPY mRNA levels seen during food deprivation. |
Gonadal steroids are known to influence food intake and weight gain. Short term vs. long term estrogen exposure may show different effects on NPY levels. Short exposure to gonadal steroids increase NPY secretion in the hypothalamus. Removal of the gonads decreases pre-pro-NPY mRNA levels in the ARC. Ovariectomised animals show increased food consumption and weight gain, with normalisation of food intake with estrogen replacement. Front Neuroendocrinol. 1996 Oct;17(4):371-401. NPY producing neurons possess estrogen receptors and prolonged chronic estrogen therapy suppresses NPY synthesis in the ARC and NPY release in the PVN. Cytokines are thought to mediate the anorexia of chronic illnesses. Interleukin-1 (IL-1) may decrease food intake by decreasing the ability of NPY to stimulate feeding. Neurosci Biobehav Rev. 1991 ;15(2):185-215. Ciliary Neurotrophic factor (CNTF), another cytokine decreases appetite when administered systemically or centrally. Neurosci Lett. 1998 Jan 2;240(1):45-9. CNTF has been shown to decrease the pro-feeding actions of NPY by suppressing NPY gene expression in ARC Endocrinology. 1998 Feb;139(2):466-73. as well as by down regulating Y1 receptor density. Regul Pept. 1998 Sep 25;75-76:391-5. |