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Methodologies
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Neuropeptide Y (NPY) mediator of feeding
Neuropeptide Y (NPY), a peptide with 36 amino acid residues, is one of
the most abundant neuropeptides in both the peripheral and the central
nervous systems. It belongs to the pancreatic polypeptide family of
peptides. (Fig. 1) Like its relatives, peptide YY (PYY) and pancreatic
polypeptide (PP), NPY is bent into hairpin configuration that is
important in bringing the free ends of the molecule together for binding
to the receptors.
Structures of Pancreatic Polypeptide Family
| NPY, human |
YPSKP |
DNPGE |
D |
A |
PA |
E |
|
DMAR |
Y |
|
YSA |
LR |
|
H |
Y |
I |
N |
L |
|
I |
TR |
Q |
R |
Y-amide |
| PYY, human |
YPIKP |
EAPGE |
D |
A |
SP |
E |
|
ELNR |
Y |
|
YAS |
LR |
|
H |
Y |
L |
N |
L |
|
V |
TR |
Q |
R |
Y-amide |
| PP, human |
APLEP |
VYPGD |
N |
A |
TP |
E |
|
QMAQ |
Y |
|
AAD |
LR |
|
R |
Y |
I |
N |
M |
|
L |
TR |
P |
R |
Y-amide |
|
Several receptor subtypes for the NPY-family peptides have been
described pharmacologically using organ preparations from different
species. The best characterized are Y1 and Y2 receptors, both of which
bind to NYP as well as PYY. The Y3 receptor has preference for NPY over
PYY, whereas a separate subtype binds most strongly to PYY. (Table 1)
Also, PP has been reported to have a distinct receptor with unique
properties. The feeding response seems to be mediated by a receptor with
unique properties.
|
| Ligands |
NPY receptor sub-types |
NPY(1-36) |
Y1, Y2, Y3 |
PYY(1-36) |
Y1, (Y2) |
[Pro34] NPY(1-36) |
Y1 |
NPY(2-36) |
Y2 |
NPY(3-36) |
Y2 |
NPY(13-36) |
Y2 |
[Leu31, Pro34]NPY(1-36) |
Y1, (Y3) |
N-Ac-[Leu28,31]NPY(24-36) |
Y2 |
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NPY exerts a wide range of effects in the central nervous system (CNS)
and the periphery.
Its CNS actions include major effects on feeding and energy expenditure,
and alterations in heart rate, blood pressure, arousal and mood. In the
periphery, NPY causes vasoconstriction and hypertension; it is also
found in the gastrointestinal and urogenital tract, implicating its
functions by action upon gastrointestinal and renal targets. In recent
studies, hypothalamic NPY has been found to play a fundamental role in
developing the features of obesity, it is a major transducer in the
pathways signalling body fat to the hypothalamus, and in regulating body
fat content. Leptin, an obese gene product, has been found to decrease
NPY gene expression in obese (ob/ob) mice. Insulin and corticosteroids
are also involved in the regulation of hypothalamic NPY synthesis, with
insulin decreasing and corticosteroids increasing NPY expression.
In the past few years, several peptide and
nonpeptide NPY receptor antagonists have
been developed. Among them, BIBP3226
(Fig. 2), a nonpeptide compound with low
molecular weight, is the most widely studied
Y1 receptor antagonist.
Other peptide antagonists (e.g., 1229U91) also show very interesting Y1
receptor antagonist properties. (Fig. 3) It is, however, unclear whether
these antagonists will specifically
inhibit NPY-evoked feeding (Fig. 3). It seems increasingly likely, with
the significance of NPY system, that it will provide the significant
therapeutic potential for treatment of obesity and other diseases.
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