AMER. ZOOL., 35:437^*45 (1995)
The Role of Peptides in Appetite Regulation Across Species'
JOHN E. MORLEY2
Geriatric Research Education and Clinical Center, St. Louis VA Medical Center, St. Louis, Missouri, and
Division of Geriatric Medicine, St. Louis University Medical School, St. Louis, Missouri
The regulation of food intake is a complex process involving
both a central feeding drive and a peripheral satiety system. The endogenous kappa opioid dynorphin, is an important central stimulator of
feeding. Opiates are involved in feeding regulation of a variety of species
including amoeba, molluscs, mammals and birds. Opioids appear to regulate a variety of behaviors necessary to allow the animal to successfully
obtain food. Some species lack an opioid feeding system. Cholecystokinin
(CCK) is the prototypic satiety agent which decreases feeding in multiple
species from molluscs to humans. CCK also enhances memory and thus
may play a role in allowing the animal to remember the details of a
successful hunt. Alterations in the photoperiod can alter the response to
satiety peptides raising the possibility that these peptides may play a role
in pre-hibernation anorexia. Other important neurotransmitters involved
in generating the feeding drive are neuropeptide Y and nitric oxide. Studies
across species suggest that the central feeding command system is the
basic feeding system, which with the organism's development of the need
for satiety periods is held in check by the introduction of a variety of
peripheral satiety systems.
SYNOPSIS.
INTRODUCTION
The regulation of food intake is a very
complex process which is central to species
survival. The complexities of food intake
are well illustrated by the moose (Alces alces)
on the shores of Lake Superior which
browses between the coastal shores and
inland areas to allow a choice of an adequate
diet balanced between aquatic plants, an
essential sodium source, and the deciduous
plants of higher caloric density (Belovsky,
1978). Food intake also needs to be regulated to decrease appropriately during times
of shortened photoperiod and the accompanying shortage of food.
It is now generally accepted that feeding
is under the control of a centralfeeding system which is held in check by a peripheral
1
From the Symposium on Comparative Gastrointestinal Endocrinology: Integration of Function presented at the Annual Meeting of the American Society
of Zoologists, 27-30 December 1992, at Vancouver,
British Columbia, Canada.
2
Address correspondence to: John E. Morley, M.D.,
St. Louis University Medical School, 1402 S. Grand
Blvd., Rm. M238, St. Louis, Missouri 63104.
satiety system (Morley, 1980). The central
feeding system is regulated by a delicate balance of the interaction between monoamines and neuropeptides. The peripheral satiety system consists of a number of
gastrointestinal peptides that are released
from the gut in response to the passage of
food and result in the termination of the
meal. The role of nutrient depletion in stimulating feeding, appears to predominantly
involve an interaction with the central feeding system.
Numerous peptides acting either as neurotransmitters or hormonal peptides have
been demonstrated to either increase or
decrease food intake (Morley, 1987). In this
review the effects of peptides on food intake
across a variety of invertebrates and vertebrates will be examined. An attempt will
be made to develop a holistic theory on the
evolutionary role of peptides in the regulation of food seeking and food obtaining
behaviors and in the modulation of food
intake. While numerous peptides have been
implicated in playing a regulatory role in
feeding, studies for the most part have been
limited to rodents. For this reason this
437
438
JOHN E. MORLEY
review will concentrate on opioid peptides
and cholecystokinin, whose effects have been
studied across a broad range of species.
MOLLUSCS AND FEEDING
Pleurobranchaea califonica is a voracious
eater, spending the majority of its life eating
anything within its vicinity. Survival of this
species is dependent on the development of
feeding inhibitory systems. One such system is the development of the egg laying
hormone, which has a dual effect of first
producing satiety and then egg laying; thus
allowing the eggs to be safely deposited in
the water without being cannibalized (Davis
et al, 1974). Another need of a perpetual
feeding organism is the ability to recognize
and not ingest potentially toxic substances.
The paracerebral neurons (PCNs) act as the
feeding command station of the pleurobranchea (London and Gillette, 1984). Noxious chemosensory stimuli, e.g., ethanol,
caused an inhibition of PCN activity and
oral veil withdrawal, thus resulting in protection from ingestion of toxic substances.
Pleurobranchea can then learn to avoid
potentially harmful situations and inhibit
PCN activity (Kovac et al, 1986).
A small number of studies have examined
the pharmacological regulation of feeding in
other molluscs. A coordinated neuronal system within the cerebral and buccal ganglia
of Limax maximus (the terrestial slug) is
responsible for initiating the feeding motor
program (FMP) in response to chemical
stimuli. (Weiland and Galperin, 1983).
When dopamine is applied to these neurons, it elicits a response similar to the FMP.
Further testing has suggested that it is a
dopamine-1 (Dl) receptor that is responsible for the endogenous triggering and sustaining of the FMP.
The effects of opiates on feeding have also
been studied in Limax maximus. Morphine, a mu opiate agonist, decreased feeding at low doses and increased ingestion at
higher doses (Kavaliers et al, 1986). The
highly specific kappa opiate agonist U50,
48 8H enhanced ingestive behavior in this
slug, as did, to a lesser extent, the mixed
mu and kappa opiate agonist, ketocyclazocine. The opiate antagonist, naloxone,
decreased these effects and a delta opiate
antagonist, also decreased free feeding. U50,
48 8H was also shown to increase the length
of the FMP (Wong et al, 1991). These findings parallel those found for opiate activation of food intake in rats (Morley et al,
1982a) and humans {Homo sapiens, Morley
et al, 1985) where the kappa opiate agonists
appear to be the most powerful activators
of food intake. In addition, studies in rats
have suggested that the initiation of food
intake involves a close interaction between
opioid and dopaminergic neurotransmitters
(Morley et al, 19806). These findings
strongly support the concept of an early evolution of opioid and dopaminergic regulation of the feed drive system (FMP).
Light tail pinch, which has been developed as a model of stress induced eating in
rats, (Rattus rattus), mice (Mus musculus),
and cats {Felis catus) (Morley, Levine et al,
1983a), has been demonstrated to increase
food intake in Limax (Kavaliers and Hirst,
1986). This increase in feeding in slugs in
response to tail pinch is blocked by the opiate antagonist, naloxone. Studies in rats have
suggested that tail pinch produces an
increase in endogenous opioid activation
primarily as an attempt to produce analgesia with a non-specific, "spillover" effect
resulting in activation of the opioid feeding
system (Morley et al, 1982a, b). Stress
induced feeding is observed in the wild in
many species and is thought to represent a
displacement phenomenon. It has been suggested that the major effect of stress may be
to produce oral behaviors with the ingestion
of food being an epiphenomenon (Levine
and Morley, 1982).
Small cardioactive peptide B (SCPB) is a
peptide that in vitro can lower the threshold
for the initiation of the FMP in Limax (Prior
and Watson, 1988). Its interactions with
dopamine and opiates have not been studied. During feeding there is an increase in
cardiac activity that appears to be due to
SCP (Welsford and Prior, 1991).
Cholecystokinin (CCK) is the prototypic
gastrointestinal hormonal satiety agent in
vertebrates. Zimering et al. (1988) have
demonstrated the presence of CCK-8 like
immunoreactivity in the opisthobranch,
mollusc, Nivanax inermis. CCK-8 inhibited
activity in buccal ganglion neurons and the
439
PEPTIDES AND APPETITE
TABLE 1. Pharmacological modulation of feeding in molluscs.
Species
Umax maximus
Clione limacine
Navanax inermis
Pleurobranchaea californica
Feeding stimulators
Small cardioactive peptide B
Dopamine (Dl)
Kappa opioids
Gamma amino butyric
expansion motoneurons which are responsible for prey capture. These findings implicate the existence of a CCK-like peptide with
an inhibitory regulatory role in feeding in
this mollusc.
While only a few studies of neurotransmitters and neurohormonal agents that regulate feeding in vertebrates have been carried out with molluscs (Table 1), the
available data suggest that the substances
involved in feeding regulation evolved early
in the evolutionary process and have been
remarkably well phyogenetically conserved.
The fact that opiates also appear to regulate
the pinocytic feeding response in Amoeba
proteus (Josefsson and Johansson, 1979)
gives further credence to this concept.
ENDOGENOUS OPIOIDS AS
MODULATORS OF VERTEBRATE
FEEDING AND FORAGING BEHAVIOR
As alluded to previously, endogenous
opioids have been demonstrated to be potent
enhancers of feeding in a variety of species.
Studies in the rat have strongly supported
the concept that the primary endogenous
opioid that enhances feeding is dynorphin
which activates the kappa opioid receptor
(Morley et ai, 19836). Besides the well
established role of opioids in stress-induced
eating, they also appear to be involved in
the modulation of food choice. They are
however, clearly not the only neurotransmitter involved in modulating feeding
behaviors.
Opiates are particularly effective in
enhancing feeding when injected into the
paraventricular and ventromedial nucleus
of the hypothalamus (Gosnell et ai, 1986).
Endogenous opioids have been considered
to play an integral role in the maintenance
of bodily homeostasis (Morley, 1983). In an
attempt to delineate how opioids may play
Feeding inhibitors
Naloxone
Cholecystokinin
Egg laying hormone
a coordinating role in satisfying the hunger
drive, my group has studied the role of
endogenous opioids in a number of different
species.
The wolf {Canis lupus) ingests predominantly ungulates. In the wild the average
wolf pack makes a kill every 4 to 7 days and
travels an average of 37.5 km between kills
(Peterson and Stephens, 1980-81). Wolves
ingest approximately more food in winter
than in summer and ingest greater total calories when provided a more caloric dense
food (i.e., purina dog chow) than when provided with a less caloric dense food (deer
meat) (Morley et al, 1983c). In the lyacon
subspecies of wolf, we found that the opiate
antagonist, naloxone, was equally effective
at reducing food intake in both summer and
winter. Naloxone produced a greater
decrease in locomotor activity in winter,
when the hunger drive is greater, than in
summer. This study suggested that opioid
neurotransmitters regulate both feeding
behavior and the locomotion necessary to
hunt for food. The opioid effect on locomotion was more marked in winter when
game is scarce and wolves may need to travel
longer distances to capture their prey.
The white-tailed deer (Odocoilens virginianus) develops a period of voluntary
hypophagia associated with body weight loss
in winter. This hypophagia is associated with
a decrease in metabolic rate and physical
activity. It is believed that this behavior
represents an energy conservation strategy
to maintain a favorable balance between
energy requirements and resources. Opiate
antagonists decreased food intake both in
summer and winter, suggesting that opioids
do not play a role in modulating the winter
hypophagia that occurs in deer (Plotka et
ai, 1985). However, opiate antagonists did
have a greater suppressive effect on activity
440
JOHN E. MORLEY
TABLE 2. Comparison of food intake and hypothalamic dynorphin levels in species that decreasefood in response
to naloxone and those that are insensitive.
Species
Naloxone sensitivity
Wolf {Canis lupus)
Woodchuck (Marmota monax)
Rat (Rattus rattus)
13-lined ground squirrel
{Spermophilus tridecemlineatus)
Raccoon (Procyon lotof)
Golden Hamster
(Mesocricetus auratus)
Mouse (Mus musculus)
Chinese Hamster
(Criteculus griseus)
Food intake
(kcal/kg/day)
Hypothalamic dynorphin
(fmol/mg protein)
+
+
+
+
60
130
170
350
NA
269
279
3,201
—
-
270
500
6,369
NA
630
1,380
NA
920
+
_
NA = not available; + decreases food to naloxone; — no response.
in winter than in summer suggesting a modulatory role for opioids on seasonal activity
patterns in deer. This is similar to the pattern observed in wolves and further supports the teleological argument that the regulation of locomotor and feeding activity
should be coupled when food is scarce in
winter and foraging distances may be greater.
Tigers {Panthera tigris) will eat large
amounts (30 to 50 kg) of meat at a single
setting to produce satiation although 5 to 7
kg daily represents average consumption
(Schaller, 1967). We studied feeding in Siberian tigers {Panthera tigris altaica). Studies
were done in 48 hr deprived animals. Naloxone decreased feeding in a dose dependent manner when the animals were given
access to their normal food (BiUington et
ai, 1985). These tigers rejected a novel food
and when the novel food was paired with
naloxone the tigers exhibited emesis. These
studies suggested that endogenous opioids
may play a role in the recognition of safe,
non-toxic food substances.
Hibernation is associated with a preparatory period of hyperphagia to increase
energy stores followed by hypophagia or
aphagia. The role of endogenous opioids in
modulating food intake has been studied in
a number of hibernating species. The woodchuck {Marmota monax) is a true hibernator which increases its body weight until
it enters hibernation. During the hypophagia period woodchucks had their food
intake suppressed by naloxone, with the
effect being more marked when the animals
were offered a preferred food (carrots)
(Nizielski et al, 1985). Similarly naloxone
decreased food intake in the 13-lined ground
squirrel {Spermophilus tridecemlineatus).
Hypophagic animals were 10 times more
sensitive to the effects of naloxone than were
animals during the hyperphagic period
(Nizielski et al., 1986). Immunoreactive
dynorphin levels were higher in the hypothalamus during the hypophagic compared
to the hyperphagic period. In another hibernating species, the golden hamster, {Mesocricetus auratus) opioid antagonism failed
to decrease food intake (Lowy and Yim,
1982). These studies suggest that at least in
some hibernating species the pre-hibernation hypophagia is not related to changes in
the opioid feeding system, but rather to an
alternative neurotransmitter system.
Opioid feeding systems have been demonstrated in numerous other species including sheep {Ovis ansmon; Baile et al, 1981),
guinea pigs Cavia poriellus, (Billington et
al., 1990), pigs {Sus scrofa domestica; Baldwin et al, 1990) domestic fowl Gallus
domesticus (Denbow and McCormack,
1990) and Japanese quail {Coturnix coturnix japonica; McCormack and Denbow,
1987). On the other hand, opioids appear
not to play a direct role in the regulation of
food intake in raccoons {Procyon lotor,
Nizielski et al, 1985) and in the Chinese
hamster {Cricetulus griseus, Billington et al,
1984). In the Chinese hamster we demonstrated a lack of classical mu or kappa opioid
binding sites. Of interest is that Chinese
hamsters tend to demonstrate minimal circadian fluctuation in feeding and show min-