Neuropeptide Y NPY

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NPY was isolated from the porcine brain by using an assay developed by Dr. Tatemoto and Professor Mutt in 1982 to detect C-terminally a-amidated peptides. Because the isolated peptide was found to consist of tyrosine in both its N- and C-terminal ends, it was named NPY. The peptide consists of a 36-amino acid residue and shows a high structural homology to peptides YY (PYY) and PP. The human NPY gene is located on chromosome 7p15.11, consists of four exons, and encodes for the 29-residue signal peptide and the 68-residue proNPY. proNPY is further processed to NPY at its N-terminal end and to the 30-residue peptide, CPON (C-terminal flanking pep-tide of NPY), at its C-terminal end (Fig. 6). Both NPY and CPON are highly conserved between species. Thus, NPY in humans and rats has an identical sequence, differing from porcine NPY in only one amino acid (position 17 is a lysine residue instead of methionine). Furthermore, human and rat CPON shows only two amino acid differences (position 19 being arginine and position 28 being serine in rat CPON).

NPY is a widely distributed neuropeptide both in the brain and in peripheral tissues, with primary localization to adrenergic neurons. In the central nervous system, localization to both the cerebral cortex and the forebrain has been reported, and a particularly high content of NPY has been observed in specific nuclei in the hypothalamus, mainly in the paraventricular nucleus and the arcuate nucleus. In these locations, the peptide seems to be of major importance for the regulation of feeding behavior and energy balance, and it is of great importance that its expression is inhibited by leptin. In the peripheral nervous system, NPY exists in almost all organs, particularly in perivascular adrenergic nerve fibers, and a major function of the neuropeptide is its involvement in the local regulation of blood flow. NPY also affects smooth muscle contractions in other locations and may be involved in the regulation of the gastrointestinal tract and the genitourinary system.

In the pancreas, NPY containing neurons are richly distributed around vessels in the exocrine portion of

36 38 68

hNPY YPSKPDNPGEDAPAEDMARYYSALRHYI N L1TRQRY* hPP APLEPVYPGDNATPEQMAQYAADLRRY1NM LTRPRY* hPYY YP1 KPEAPGEDASPE E LNRYYASL RHYLNLVTRQRY* hCPON SSPETLI SD LLMREST E NVPRTRLEDPAMW

Figure 6 Schematic representation of the NPY gene and proNPY. Exons 1 and 2 encode the signal peptide and exons 2-4 encode the proNPY. At the bottom of the figure are the amino acid sequences of human VIP, human PP, human PYY, and human CPON. * indicates a C-terminal NH2 group.

the islets, and NPY nerves also innervate the islets. Because NPY is colocalized with tyrosine hydroxylase both in islet nerves as well as in nerve cell bodies in the celiac ganglion, it is supposed that NPY is an islet sympathetic neuropeptide. This is supported by findings that chemical sympathectomy by 6-hydroxydopa-mine substantially reduces the pancreatic NPY innervation in islets. However, NPY has also been shown to be colocalized with VIP in islet nerves in the pig, suggesting that nonadrenergic NPY nerves might also exist. In addition, under some conditions, as in insulin resistance, islet b cells also seem to express NPY. NPY therefore might function both as a sympathetic and as a parasympathetic neuropeptide and as a local autocrine islet peptide. A main function is, however, the role of NPY as a sympathetic neurotransmitter.

NPY has been shown to inhibit glucose-stimulated insulin secretion, i.e., to exert a sympathetic-like effect, in several studies both in vivo and in vitro. Six different NPY receptors have been cloned (Y1, Y2, Y3, Y4, Y5, and Y6 receptors). Some of these receptors show affinity for PYY and/or PP. These receptors are all of the seven transmembranous domain, G-protein-cou-pled type but show differences in localization and characteristics with regard to the spectra of affinity for the peptides in the NPY-PP-PYY family. In insulin producing cells, most evidence shows that it is the Y1 receptor subtype that mediates islet actions of NPY. Thus, analogs ofPYY that are specific for Y1 receptors mimic the effects of NPY, and a specific Y1 receptor antagonist prevents NPY from inhibiting insulin secretion. The gene for the human Y1 receptor is located at chromosome 4q31.3-32, and the full-length receptor consists of a 384-amino acid residue. The human and mouse forms of the receptor show 93% identity, suggesting a high degree of conservation of the Y1 receptor during evolution. Studies have indicated that two different isoforms of the Y1 receptor exist, called the Y1a and Y1b receptors, respectively. They show a high degree of identity, differing in only seven amino acids, and they are encoded by the same gene and are generated by alternative splicing. The Y1b receptor seems, however, to be expressed mainly during embryogenesis and therefore might not be of relevance after birth.

The mechanism underlying the inhibition by NPY of glucose-stimulated insulin secretion is not fully established but seems to involve inhibition of adeny-late cyclase with reduced formation of cAMP. However, distal mechanisms in relation to the formation of cAMP also seem to be involved because insulin secretion stimulated by a cAMP analog is inhibited by NPY, as demonstrated in a perfused rat pancreas model. The physiological importance of NPY for islet function remains to be established. One study has demonstrated that immunoneutralization of NPY in isolated islets leads to increased insulin secretion, which would suggest a physiological inhibitory effect of islet NPY on insulin secretion. However, it is not clear whether this is exerted through its neural localization or through its expression in islet b cells, which occurs under some conditions. Furthermore, results from studies using a Yl-receptor-specific antagonist or NPY-deficient mice have found no effect on glucose and insulin levels, and the NPY-deficient mice do not develop diabetes or other abnormalities in glucose homeostasis. However, the issue of whether NPY contributes to sympthetically induced regulation of islet function has not been examined in these mice. Therefore, the role of NPY in the regulation of islet function remains to be established.

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