Role
of bombesin-related peptides in the
control of food intake
In 1970, Erspamer and co-workers
(1,14)isolated and characterized
the tetradecapeptide bombesin
(BN) from the skin of amphibian
frog Bombina bombina. Subsequently,
several BN-like peptides have
been identified in mammals,
consisting of various forms
of gastrin-releasing peptide
(GRP) and/or neuromedin B (NMB),
together with their distinct
receptor subtypes. It has been
proposed that BN-related peptides
may be released from the gastrointestinal
(GI)-tract in response to ingested
food, and that they bridge the
gut and brain (through neurocrine
means) to inhibit further food
intake. Conversely, the suppression
of release of BN-like peptides
at relevant brain nuclei may
signal the initiation of a feeding
episode. The present review
will describe recent pharmacological,
molecular, behavioral and physiological
experiments, supporting the
contention that endogenous BN-related
peptides do indeed influence
ingestive behaviors. Particular
attention is focused on the
relationship between these peptides
in the peripheral compartment
and their impact on central
circuits using GRP and/or NMB
as transmitters. In addition,
however, we will point out various
caveats and conundrums that
preclude unequivocal conclusions
about the precise role(s) of
these peptides and their mechanism(s)
of action. We conclude that
BN-related peptides play an
important role in the control
of food intake, and may contribute
to ingestive disruptions associated
with anorexia (anorexia nervosa,
AIDS and cancer anorexia), bulimia,
obesity and depression. Hence,
pharmacological targeting of
these systems may be of therapeutic
value.
Merali
Z, McIntosh J, Anisman H. Role
of bombesin-related peptides
in the control of food intake.
Neuropeptides 1999 Oct;33(5):376-86
Proadrenomedullin
N-terminal 20 peptide (PAMP)
elevates blood glucose levels
via bombesin receptor in mice
We found a potent hyperglycemic
effect of proadrenomedullin
N-terminal 20 peptide (PAMP)
after intra-third cerebroventricular
administration at a dose of
10 nmol in fasted mice. PAMP
has four homologous residues
with bombesin (BN), a hyperglycemic
peptide. PAMP showed affinity
for gastrin-releasing peptide
preferring receptor (GRP-R)
and neuromedin B preferring
receptor. The PAMP-induced hyperglycemic
effect was inhibited by [D-Phe(6),
Leu-NHEt(13), des-Met(14)]-BN
(6-14), GRP-R specific antagonist,
indicating that the hyperglycemic
effect is mediated at least
in part via GRP-R. Furthermore,
pretreatment of alpha-adrenergic
blocker inhibited the PAMP-induced
hyperglycemia and hyperglucagonemia,
suggesting that the increase
of glucagon secretion through
alpha-adrenergic activation
is involved in this hyperglycemic
effect of PAMP.
Ohinata
K, Inui A, Asakawa A, Wada K,
Wada E, Yoshikawa M Proadrenomedullin
N-terminal 20 peptide (PAMP)
elevates blood glucose levels
via bombesin receptor in mice.
FEBS Lett 2000 May 12;473(2):207-11
Inhibition of gastric
emptying by bombesin-like peptides
is dependent upon cholecystokinin-A
receptor activation
The amphibian peptide bombesin
(BN) and the related mammalian
peptides gastrin-releasing peptide
(GRP) and neuromedin B (NMB)
inhibit gastric emptying in
rats. Exogenous administration
of BN stimulates the release
of cholecystokinin (CCK), a
gastrointestinal peptide that
also potently inhibits gastric
emptying. To determine whether
the inhibition of gastric emptying
by BN-like peptides is mediated
by a CCK-dependent mechanism,
we examined the ability of the
CCK-A receptor antagonist, devazepide,
to block the inhibition of saline
gastric emptying produced by
BN, GRP18-27 and NMB. Using
the same dosages as in the gastric
emptying experiment, we also
evaluated the effect of devazepide
on feeding suppression produced
by systemically administered
BN. Our results showed that
devazepide completely blocked
the suppression of gastric emptying
produced by BN, GRP18-27 and
NMB but had no effect on BN-induced
suppression of food intake.
These results suggest that BN-like
peptides inhibit gastric emptying
through an indirect mechanism
that is dependent upon CCK-A
receptor activation. In contrast,
the suppression of food intake
by BN, in this experimental
paradigm, is independent of
CCK-A receptors.
Ladenheim
EE, Wohn A, White WO, Schwartz
GJ, Moran TH. Inhibition
of gastric emptying by bombesin-like
peptides is dependent upon cholecystokinin-A
receptor activation.
Regul Pept 1999 Oct 22;84(1-3):101-6
Caudal hindbrain
neuromedin B-preferring receptors
participate in the control of
food intake
Recent studies have identified
two subtypes of bombesin (BN)
receptors in the rat central
nervous system: gastrin releasing-peptide
(GRP) preferring and neuromedin
B (NMB) preferring. To investigate
a role for the NMB-preferring
receptor subtype in feeding
suppression elicited by fourth
ventricular (4V) BN administration,
we evaluated the ability of
a selective NMB-preferring receptor
antagonist, BIM-23127, to block
suppression of glucose intake
produced by 4V BN (10 pmol).
Our results showed that 4V administration
of BIM-23127 dose dependently
antagonized the suppression
of glucose intake produced by
4V BN. In addition, 4V administration
of BIM-23127 alone increased
glucose intake above that observed
in the baseline condition. These
results support a role for the
NMB-preferring BN receptor subtype
in the suppression of intake
produced by 4V BN administration
and suggest that endogenously
released NMB participates in
ingestive control.
Ladenheim
EE, Taylor JE, Coy DH, Carrigan
TS, Wohn A, Moran TH. Caudal
hindbrain neuromedin B-preferring
receptors participate in the
control of food intake. Am J
Physiol 1997 Jan;272(1 Pt 2):R433-7
Rational design of a peptide
agonist that interacts selectively
with the orphan receptor,
bombesin receptor subtype
3
The orphan receptor, bombesin
(Bn) receptor subtype 3 (BRS-3),
shares high homology with
bombesin receptors (neuromedin
B receptor (NMB-R) and gastrin-releasing
peptide receptor (GRP-R)).
This receptor is widely distributed
in the central nervous system
and gastrointestinal tract;
target disruption leads to
obesity, diabetes, and hypertension,
however, its role in physiological
and pathological processes
remain unknown due to lack
of selective ligands or identification
of its natural ligand. We
have recently discovered (Mantey,
S. A., Weber, H. C., Sainz,
E., Akeson, M., Ryan, R. R.
Pradhan, T. K., Searles, R.
P., Spindel, E. R., Battey,
J. F., Coy, D. H., and Jensen,
R. T. (1997) J. Biol. Chem.
272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14)
has high affinity for BRS-3
and using this ligand showed
BRS-3 has a unique pharmacology
with high affinity for no
known natural Bn peptides.
However, use of this ligand
is limited because it has
high affinity for all known
Bn receptors. In the present
study we have attempted to
identify BRS-3 selective ligands
using a strategy of rational
peptide design with the substitution
of conformationally restricted
amino acids into the prototype
ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14)
or its d-Phe(6) analogue.
Each of the 22 peptides synthesized
had binding affinities determined
for hBRS-3, hGRPR, and hNMBR,
and hBRS-3 selective ligands
were tested for their ability
to activate phospholipase
C and increase inositol phosphates
([(3)H]inositol phosphate).
Using this approach we have
identified a number of BRS-3
selective ligands. These ligands
functioned as receptor agonists
and their binding affinities
were reflected in their potencies
for altering [(3)H]inositol
phosphate. Two peptides with
an (R)- or (S)-amino-3-phenylpropionic
acid substitution for beta-Ala(11)
in the prototype ligand had
the highest selectivity for
the hBRS-3 over the mammalian
Bn receptors and did not interact
with receptors for other gastrointestinal
hormones/neurotransmitters.
Molecular modeling demonstrated
these two selective BRS-3
ligands had a unique conformation
of the position 11 beta-amino
acid. This selectivity was
of sufficient magnitude that
these should be useful in
explaining the role of hBRS-3
activation in obesity, glucose
homeostasis, hypertension,
and other physiological or
pathological processes.
Mantey
SA,et al. J Biol Chem 2001
Mar 23;276(12):9219-29
Mice lacking bombesin
receptor subtype-3 develop
metabolic defects and obesity
Mammalian bombesin-like
peptides are widely distributed
in the central nervous system
as well as in the gastrointestinal
tract, where they modulate
smooth-muscle contraction,
exocrine and endocrine processes,
metabolism and behaviour.
They bind to G-protein-coupled
receptors on the cell surface
to elicit their effects.
Bombesin-like peptide receptors
cloned so far include, gastrin-releasing
peptide receptor (GRP-R),
neuromedin B receptor (NMB-R),
and bombesin receptor subtype-3
(BRS-3). However, despite
the molecular characterization
of BRS-3, determination
of its function has been
difficult as a result of
its low affinity for bombesin
and its lack of an identified
natural ligand. We have
generated BRS-3-deficient
mice in an attempt to determine
the in vivo function of
the receptor. Mice lacking
functional BRS-3 developed
a mild obesity, associated
with hypertension and impairment
of glucose metabolism. They
also exhibited reduced metabolic
rate, increased feeding
efficiency and subsequent
hyperphagia. Our data suggest
that BRS-3 is required for
the regulation of endocrine
processes and metabolism
responsible for energy balance
and adiposity. BRS-3-deficient
mice provide a useful new
model for the investigation
of human obesity and associated
diseases.
Ohki-Hamazaki
H, et al. Nature 1997 Nov
13;390(6656):165-9
Circulating
Ghrelin Levels Are
Decreased in Human
Obesity
