Physiology & Behavior 81 (2004) 719 – 733
Endocrine controls of eating: CCK, leptin, and ghrelin
Nori Geary*
E.W. Bourne Laboratory, Weill Medical College of Cornell University, White Plains, NY 10506, USA
Abstract
The peripheral physiological and central nervous mechanisms contributing to the control of eating present formidable challenges to
experimental analysis. One of the most productive approaches to these challenges has been endocrinological. This review introduces the
endocrine control of eating by considering three hormonal signals that have been hypothesized to control hunger or satiation,
cholecystokinin (CCK), leptin, and ghrelin. The roles of these molecules in humans and in rodents are considered against a set of criteria
established in classical endocrinology for establishing physiological endocrine action. It is concluded that according to these criteria,
CCK’s satiating action in humans is the best-established physiological endocrine action. In contrast, support for endocrine actions of leptin
in satiation and of ghrelin in hunger is incomplete, and areas urgently requiring further research are identified. Finally, a review of work
on these three hormones suggests the utility of a new conceptual scheme for understanding the endocrine control of eating. This scheme
distinguishes between endocrine effects in which the stimuli for hormonal secretion and the effect of secretion on eating are tightly
coupled and endocrine effects in which one or both of these links is uncoupled. The implications of this concept for research design and
interpretation of data are discussed.
A vast literature links endocrine systems to the control of eating behavior. This is fortunate for ingestive science. Endocrinology is a welldeveloped discipline with an impressive armamentarium of intellectual and technical tools. In contrast, ingestive science, i.e., the study of
eating, drinking, and drug use, is at a more rudimentary stage of development. My general thesis here is that the adaptation and application of
some of the well-accepted intellectual tools of endocrinology is likely to accelerate progress in ingestive science.
The organization of the review is threefold. First, the treatment of endocrine controls of eating is selective. Just three hormones, CCK,
leptin, and ghrelin, are considered. It is not clear that these are the three most important endocrine controls of eating, but they are each
certainly interesting candidates, and comparisons among them are instructive. Second, I argue for the utility of the application of classical
endocrine criteria for the identification of physiological effects of hormones, as adapted to eating behavior. This is done by introducing these
criteria, considering each hormone’s status with respect to them, and identifying the areas where relevant evidence is currently available or is
lacking. Third, I argue for the utility of making explicit the distinction between endocrine actions in which the stimuli for hormonal secretion
and the effect of secretion on eating are tightly coupled and endocrine actions in which these links are uncoupled. This concept is assembled
inductively in the course of the review.
D 2004 Elsevier Inc. All rights reserved.
Keywords: Endocrine controls; CCK; Leptin; Ghrelin
1. Identification of physiological effects of hormones on
eating
Endocrinology evolved into a distinct research discipline
and medical specialty in the first half of the last century
[9,35,47,58]. Endocrinology is based on a particular type of
control mechanism, i.e., those involving the secretion of
signaling molecules into the blood, their transport in the
* Institute of Animal Sciences, Swiss Federal Institute of Technology
(ETH), Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. Tel.: +411655-7424x7428; fax: +41-1655-7206.
E-mail address: [email protected] (N. Geary).
0031-9384/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.physbeh.2004.04.013
circulation to distant organs, and the initiation of physiological effects via the activation of specific receptors. As the
understanding of these processes has grown, there have
been developments in the definition of a hormone and the
standards of evidence or criteria for identification of hormonal mechanisms [9,37]. In addition, criteria for identifying particular signaling molecules as hormones and criteria
for identifying particular effects of these molecules as
normal, physiological effects take slightly different forms.
Table 1 lists a version of these criteria for the identification
of particular effects of hormones as physiological effects.
The next sections of this review (1) evaluate the physiological statuses of the effects on eating of cholecystokinin
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N. Geary / Physiology & Behavior 81 (2004) 719–733
Table 1
Criteria for the identification of physiological effects of hormones on eating
Secretion
Receptors
Physiological
dose
Removal and
replacement
Antagonism
Some parameter of hormone secretion is associated with
a change in eating (the ‘‘eating effect’’).
Cognate receptors for the molecule are expressed at its
site(s) of action.
Intravenous infusions of the hormone that reproduce the
secretion patterns of the endogenous hormone at the
critical receptors that are associated with the eating
effect produce the eating effect, either alone or together
with other endogenous stimuli.
(a) Removal of the hormone or of the receptor
population mediating the eating effect should prevent
the eating effect.
(b) When the hormone has been removed, intravenous
replacement of the hormone at the physiological dose
should normalize the effect.
Intravenous infusion of a selective and potent antagonist
to the hormone at the time that the effect normally
occurs, or administration by another route that reaches
the critical receptors at that time, should (a) prevent the
effect of replacement of the hormone at the
physiological dose and (b) prevent the effect of the
endogenous hormone.
Note that a hormone may have several effects on eating and that the criteria
must be applied separately in each case. For example, the possibilities that
decreases in the hormone stimulate eating and that increases in it inhibit
eating, or that increase in a hormone both terminate ongoing eating and
inhibit eating during the intermeal interval, are all separate hypotheses.
(CCK), leptin, and ghrelin against these criteria and (2)
discuss several difficulties and subtleties that must be
considered in the application of the criteria. Each discussion
begins with a specific statement of the hypothesis(es) at risk.
This is for two reasons. First, eating behavior has at least
four functional phases, and a particular hormone may affect
one of these, but not the others, or affect them differently.
The four phases are (1) hunger, the initiation of eating at
meal onset (hunger); (2) the maintenance of eating during
the meal; (3) satiation, the termination of eating at meal end;
and (4) postprandial satiety, the inhibition of eating during
the postprandial intermeal interval (this terminology follows
that of Blundell [13] and Smith [78]). Second, in at least one
of the cases considered, important species differences have
emerged, which are better treated separately.
2. CCK
The hypothesis is that hormonal CCK released from the
small intestine during meals selectively signals satiation.
This function seems selective to satiation because CCK
injection reduces meal size but usually either fails to affect
the intermeal interval or shortens it. Indeed, when CCK was
injected during every spontaneous meal by remotely controlled intraperitoneal catheters, there was no tolerance in
the satiating effect over several days, but intermeal intervals
were shortened so that there was no decrease in total food
intake after the third day of infusions [89]. The CCK
satiation hypothesis is considered separately for humans
and for experimental rodents because research has led to
different conclusions.
2.1. CCK and satiation in humans
2.1.1. Secretion
Liddle et al. [52] developed the first sensitive and
specific assay for CCK and reported that the ingestion of
mixed meals, casein, amino acid or glucose solutions, or
lipid emulsions led within minutes to similar marked
increases in plasma CCK concentration (Fig. 1, top panel).
Thus, CCK is secreted sufficiently rapidly to function as a
satiation signal in humans. Prandial CCK secretion has been
reported to be markedly greater in women than in men [66],
which may be relevant to the apparent sexual differentiation
of CCK satiation [28,30,43].
2.1.2. Receptors
CCK’s biological actions are mediated by cell-surface
membrane receptors on its target cells [49,50]. CCK receptors are widespread in the gastrointestinal tract and also
occur in the pancreatic acinar cells, the gall bladder, and the
brain. Moran and Ladenheim [62] and Moran et al. [63]
identified two subtypes of CCK receptors with different
pharmacological characteristics and different tissue distributions in the periphery and CNS: CCKA receptors (or
CCK1 receptors, CCK1R), which have two affinity states,
and CCKB receptors (CCK2R).
2.1.3. Physiological dose
The work of Liddle [49,50] and Liddle et al. [51,52] on
CCK’s effect on gall bladder contraction serves as an
excellent model for the consideration of the investigation
of endocrine controls of eating. These investigators first
established an intravenous infusion procedure that mimicked prandial changes in plasma CCK concentrations and
then compared the effects of meals and of exogenous CCK
administered at the physiological dose on gall bladder
contraction, as indicated by abdominal ultrasonography
[52]. The results clearly indicate that prandial gall bladder
contraction meets the physiological dose criterion for a
physiological effect of prandial hormonal CCK release
(Fig. 1, middle panel).
Attempts to use this strategy to test the satiating action of
CCK have had mixed results. Almost all early reports that
intravenously infused CCK-8 produces satiation in humans
used pharmacological doses (see Refs. [43,79 – 81] for
reviews). The lowest effective dose in these studies was
between 0.8 and 1.7 pMol/kg/min CCK-8 [31], which is
much larger than the physiological dose of 0.2 pMol/kg/min
established by Liddle et al. [52]. Importantly, however, even
these pharmacological doses inhibit feeding without any
subjective or physical side effects [79 – 81]. In two studies
published in 1995, however, apparently, physiological doses
of CCK were sufficient to reduce meal size in humans
(Table 2). In the first of these landmark studies, Ballinger et
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Table 2
Intravenous infusion of physiological doses of CCK reduces meal size in
humans
Infusion
Meal size (mean F S.E.M.)
Saline
Ballinger
et al. [6]
Leiverse
et al. [54]
CCK
Unit P
0.72 pMol/kg/min 6418 F 673 5092 F 665 kJ
CCK-8
0.24 pMol/kg/min 346 F 31
282 F 29 g
CCK-33
< .03
< .05
In the Ballinger et al. [6] study, participants were four men and two women,
all of normal weight (BMI 21 – 25 kg/m2). Infusions were begun at
2000 h after an 8-h fast. After 25 min, the participants were offered a meal of
meat, rice, bread, cake, chocolate, and crisps; 400 ml of water was drunk
with the meal.
In the Lieverse et al. [54] study, participants were 10 normal-weight women
(BMI 22 F 3 kg/m2) and 8 healthy obese women (BMI 39 F 2 kg/m2).
Infusions were begun at 0800 h after an overnight fast. After 60 min, the
participants consumed a 132-kcal preload of bananas, followed 15 min later
by a banana-shake meal (bananas were used because they do not elicit CCK
secretion). Ideal, rather than actual, body weight was used to compute
dosages for obese women because this resulted in comparable plasma levels
in the two groups.
al. [6] reported that intravenous infusions of 0.72 pMol/kg/
min CCK-8 reduced the size (in kJ) of a buffet meal about
20% in a group of normal-weight men and women. A
preliminary study had indicated that this infusion produced
similar plasma CCK concentrations as did the ingestion of a
similar meal. In the second study, Lieverse et al. [54]
reported that intravenous infusion of only 0.24 pMol/kg/
min CCK-33 significantly reduced both the size of a singlefood test meal, again by about 20%, and postprandial
‘‘desire to eat’’ in a group of lean and obese women. This
dose increased plasma CCK concentration from about 2 to
about 10 –14 pMol/l, which was the same increase reported
to accompany the ingestion of a mixed meal using the same
CCK radioimmunoassay ([26]; although it is somewhat
higher than typically reported to accompany meals). These
two studies indicate that, at least under some experimental
conditions, CCK satiation meets the physiological dose
criterion for a hormonal effect.
The cause of the apparent discrepancies among these
experiments is not clear. Both of the two studies described
above, as well as most previous experiments, attempted to
maximize the satiating potency of CCK by using a preload
design (Ballinger et al. [6] had participants drink 200 ml
water at the beginning of the meal, and Lieverse et al. [54]
served a small banana appetizer; neither of which should
elicit CCK secretion). Such preloads appear efficacious;
Fig. 1. Endocrine action of CCK on gall bladder contraction in humans. Top
panel: Ingestion of a meal elicits an increase in plasma CCK concentration
and is associated with the contraction of the gall bladder. Middle panel:
Intravenous infusion of 0.2 pMol/kg/min CCK-8 mimics the initial prandial
increase in plasma CCK and is sufficient to produce normal prandial gall
bladder contraction in men. Bottom panel: Oral administration of 10 mg of
the CCK1R antagonist devazepide during the meal prevents prandial gall
bladder contraction. Upper and middle panels are from Ref. [52]; lower
panel is from Ref. [51]; used with permission.
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N. Geary / Physiology & Behavior 81 (2004) 719–733
when Lieverse et al. [53] omitted the preload, they obtained
only an insignificant 13% decrease in meal size. Nor is the
difference in the molecular form of CCK used likely to have
been important. CCK-8 and CCK-33 have similar affinities
for CCK receptors and similar potencies in most biological
contexts [50]. CCK-33 is degraded more slowly by the liver
than CCK-8 [22], but this difference is not likely to be
significant here because Lieverse et al. [54] demonstrated
that their infusions did not elevate plasma CCK concentrations more than did meals.
2.1.4. Removal and replacement
There is no selective surgical technique for the removal
of the intestinal cells secreting CCK. Some spontaneous
mutations of the CCK1R gene, however, indicate that
missense mutations of this gene produce a phenotype of
obesity and gallstones (the latter due to a flaccid gall
bladder; [55,59]). These data are consistent with this criterion but cannot be considered compelling evidence because
of the numerous complications that limit the interpretation
of phenotypes arising from gene deletions (these complications are considered further below).
2.1.5. Antagonism
Liddle et al. [51] continued their study of CCK’s role in
meal-stimulated exocrine pancreatic secretion by testing
intravenous infusions of an antagonist of the CCK1 receptor (CCK1R), devazepide (formerly designated L-364,718
or MK-329). Oral administration of 10 mg devazepide
completely prevented gall bladder contraction stimulated
either by meals or by intravenous infusions of CCK-8 that
produced high physiological plasma CCK concentrations
(Fig. 1, bottom panel). These data beautifully fulfill the
antagonism criterion for a physiological effect of CCK in
prandial gall bladder contraction in humans [51]. Shortly
thereafter, Beglinger et al. [10] and Matzinger et al. [57]
used an analogous strategy to demonstrate that the prandial
antagonism of CCK1R by intravenous infusion of the
antagonist loxilumide (1) blocks the satiating effect of
intraduodenal infusions of fat emulsions, which stimulate
endogenous CCK secretion, (2) increases the perception of
hunger and decrease the perception of fullness during
meals, and (3) increases meal size (Fig. 2). These data
indicate that CCK satiation meets the antagonism criterion
in humans.
2.2. CCK and satiation in rats and mice
2.2.1. Secretion
There little evidence that CCK is secreted into the blood
during meals in rats or mice. Using the assay developed by
Liddle et al. [52], Yox et al. [94] have shown that intraduodenal infusions of oleate and other nutrients first increased plasma CCK only after about 30 min, which is
longer than the typical meal duration in rats. In contrast,
Mamoun et al. [56], using reverse-phase high-performance
Fig. 2. The CCK1R antagonist loxiglumide antagonizes the satiation action
of endogenous CCK in humans. Top panel: Loxiglumide blocks the
satiating action of endogenous CCK stimulated by intraduodenal infusion
of fat emulsion. Normal-weight adult males began a noontime lunch buffet
4 h after a standard breakfast, 90 min after beginning an intravenous
infusion of loxiglumide (10 Amol/kg-h) or saline, 60 min after an
intraduodenal infusion of corn oil or saline (0.4 ml/min), and 20 min after
an oral preload of 400 ml of a low-fat banana milkshake. The infusions
were continued throughout the meal. Intraduodenal fat infusion significantly reduced the size of the lunch meal (expressed as total energy content
of the various foods) without producing physical or subjective side effects,
and this inhibition of eating was reversed by loxiglumide infusion. Bottom
panel: Loxiglumide stimulates eating. Normal-weight adult males began a
noontime lunch buffet 4 h after a standard breakfast and 60 min after
beginning an intravenous infusion of loxiglumide (22 Amol/kg-h) or saline.
Infusions were continued throughout the meal. Loxiglumide significantly
increased meal size without affecting the participants’ enjoyment of their
meals or their subjective sense of normal satiation. Upper panel is from Ref.
[57]; lower panel is from Ref. [10]; used with permission. *Significantly
different from other conditions.
liquid chromatographic assay, were able to detect three- to
fourfold increases in plasma CCK during meals in rats.
Because Mamoun et al. [56] delivered food by intraoral
infusion, which artificially determines the ingestion rate, it
N. Geary / Physiology & Behavior 81 (2004) 719–733
would be useful to repeat these tests in naturally eating
animals. Nevertheless, their data indicate that hormonal
CCK is a plausible satiation signal under at least some
conditions in rats.
2.2.2. Receptors
The satiating actions of intestinal CCK in the rats arise
from the activation of peripheral, low-affinity CCK1R, most
likely localized in the circular muscle layer of the pyloric
sphincter or nearby vagal afferent nerve endings [62,81,79].
Direct evidence for this localization comes from the demonstration of Cox [18] that CCK inhibits eating and that the
CCK1R antagonist devazepide stimulates eating more effectively when infused via the superior pancreaticoduodenal
artery, which perfuses these sites, than via the jugular vein
(Fig. 3).
2.2.3. Physiological dose
In contrast to the human data reviewed above, intravenously infused CCK inhibited eating much less effectively in rats and dogs than it stimulated pancreatic
exocrine secretion [69,71]. Furthermore, intravenous infusion of a CCK antibody reduced pancreatic exocrine
secretion but failed to affect eating [72]. In addition, the
satiating potency of some intraduodenal nutrient infusions
that did not elicit CCK secretion was reversible by
CCK1R antagonism with devazepide [14]. One possible
explanation of these data is that CCK inhibits eating in
Fig. 3. Superior pancreaticoduodenal (SPD) artery injection of the CCK1R
antagonist devazepide stimulates eating in rats at doses that are ineffective
when infused via the jugular vein (intraventricular). Injections were done
immediately before the 15-min access to 30% sucrose solutions after a
6-h food deprivation during the light phase. Open bars, control; filled bars,
devazepide. The superior pancreaticoduodenal artery perfuses the pyloric
region of the stomach and the proximal small intestine. *Significantly
different from control. From Ref. [18], used with permission.
723
rats via a paracrine, rather than via an endocrine, mode of
action. This conclusion is directly supported by the
finding that the satiating potency of intraperitoneally
injected CCK was markedly larger than that of CCK
intravenously infused into the hepatic portal vein [34,83].
The close proximity of the CCK-secreting cells in the
small intestine to the pyloric site of the crucial receptors
for satiation is also consistent with a paracrine mode of
action. The prandial changes in local CCK concentration
at these receptors are unknown, however; thus, whether a
physiological dose of exogenous CCK is sufficient to
elicit satiation via this paracrine mechanism has not been
investigated.
2.2.4. Removal and replacement
The effects of the absence of CCK have not been
described in rats. As for humans, there are data about
genetic defects in CCK1R. The Otsuka Long – Evans fatty
rat bears a null mutation of the CCK1R gene and displays a
phenotype including chronically increased meal size, increased food intake, obesity, and diabetes [61]. In contrast,
however, CCK1R knockout mice do not display hyperphagia, obesity, or diabetes [45]. It is possible that the
difference in these models has to do with brain, rather
than hormonal, CCK. That is, in the OLETF rat, the lack of
brain CCK1R is associated with the overexpression of the
orexigenic peptide NPY in the dorsomedial hypothalamus,
whereas in the mouse, it is not yet clear that this is the case
[12]. The extent of the involvement of deranged NPY
signaling in the phenotype of the OLETF rat is not yet
clear. In summary, studies of CCK1R knockout animals
have not yet provided evidence that abdominal CCK1R
signaling alone is necessary for normal control of meal
size. It would support this hypothesis if CCK1R knockout
mice displayed increased meal size, but this has not yet
been tested. The general point is that most signaling
molecules, CCK included, have a variety of roles in a
variety of tissues. Hence, it is unwise to interpret changes
in complex phenotypes, such as eating in animals with
knockouts of signaling systems, as the specific result of the
defect in a specific site. Some other complications in the
interpretation of genetic models are considered in the
Leptin section.
The sham-feeding preparation, in which ingested food
drains from gastric cannulas, provides an acute removal
strategy. Rats that are offered palatable food to sham feed
after an overnight food-deprivation sham feed essentially
indefinitely, and CCK injection both terminates sham
feeding and reproduces the species typical behavioral
display of postprandial satiety [3,33]. These data are
strong support that CCK satiation meets this removal
aspect of the criterion. It is not clear if the data meet
the replacement aspect because it is not certain if the
doses of CCK required to produce satiation were physiological. The production of satiation in sham-feeding rats
by intraduodenal infusions of CCK secretogogues and the
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reversal of this satiation by pretreatment with devazepide
[14,94], however, may be considered support for a variant
of the replacement criterion.
2.2.5. Antagonism
This criterion was amply fulfilled in the rat by several
experiments, around 1990, that demonstrated that the antagonists of CCK1R, but not of CCK2R, (1) blocked the
satiating effects of exogenous CCK and (2) increased meal
size [18,21,40,60,70,82]. There are now dozens of such
reports [79]. One result is shown in Fig. 3.
2.3. Formulation: CCK is a fully coupled endocrine
satiation signal
The criteria for a physiological endocrine effect have
been investigated in more detail for CCK than for any
other hypothesized hormonal control of eating. Available
evidence indicates that CCK released from the small
intestine during meals is a physiological control of satiation
in both rats and humans, but that CCK’s mode of action is
paracrine in the rat and endocrine in humans. The support
for these hypotheses is so strong that hypotheses have been
considered to be proven [79 – 81]. Nevertheless, not all the
classical criteria enumerated in Table 1 are met for either
species.
CCK’s satiation signaling mechanism in humans may
be characterized as a fully coupled endocrine control of
eating. This is because discrete, apparently time-locked,
causal physiological cascades appear to link (1) a specific
food stimulus with increased CCK secretion into the blood
and (2) increased plasma CCK with a change in eating,
i.e., the termination of ongoing eating, or satiation. The
situation in rats seems identical, except for the mode of
signaling (a distinction that some authors consider of little
interest [35]). The linkage is very tight, or coupled: The
stimulus producing CCK secretion (Link 1) is the presence
in the small intestine of nutrients that were ingested just
minutes prior, and satiation ensues just a few minutes after
CCK secretion (Link 2). As described below, some other
endocrine controls of eating have very different functional
characteristics, with the first, the second, or both links of
the chain loosely linked, or uncoupled. These variations
are schematized in Fig. 4. In a fully coupled control, such
as CCK’s, the close temporal associations among eating,
secretion, and satiation should inform the designs and
interpretations of experimental dissection of the phenomena. For example, (1) knowledge of the adequate stimuli for
CCK secretion and their temporal dynamics facilitates the
manipulation of secretogogues; (2) experiments in which
the natural temporal patterns are not closely mimicked,
e.g., by administering CCK long before meal onset or by
producing unnatural rates of increases in CCK concentrations, fail to recapitulate normal physiology and, in the
worst case, may produce artifactual results; and (3) a
neuronal correlate of increased peripheral CCK that occurs
Fig. 4. Endocrine controls may be considered to function through a chain of
two stimulus – response links. In the first link, a stimulus for hormone
secretion is linked to hormone secretion. In the second link, hormone
secretion is the stimulus and eating is the response. Each of these links can
be considered tightly coupled (top panel, filled arrows) or uncoupled
(bottom panel, unfilled arrows). The first link is coupled when there are
discrete, highly time-locked causal physiological cascades between the
stimulus for hormone secretion and its secretion. Similarly, the second link
is coupled when there is a time-locked causal physiological cascade
between changed plasma hormone levels and hunger, satiation, or another
parameter of eating. In a fully coupled endocrine control of eating, both
links are coupled; in an uncoupled endocrine control, one or both links is
uncoupled. As explained in the text, CCK satiation is apparently fully
coupled, whereas leptin satiation and ghrelin secretion appear uncoupled.
more slowly than satiation cannot be considered a part of
the cause of satiation.
3. Leptin
Because available evidence indicates that leptin selectively affects meal size and not meal number [23,25,42], the
hypothesis considered here is that leptin signals meal-ending
satiation. In contrast to CCK, however, chronically decreased meal size induced by chronic leptin treatment is
N. Geary / Physiology & Behavior 81 (2004) 719–733
725
not compensated for by changes in meal frequency [23,42].
This suggests that leptin (1) may inhibit hunger and meal
initiation as well as stimulate satiation and (2) may be more
relevant to body weight than CCK is. So far, there appears
to be no reason not to consider the leptin’s satiating effects
in humans and in rats and mice together.
3.1. Secretion
Adipocytes are the main source of circulating leptin, with
leptin secretion increasing with increasing adipocyte size
[1,27,48]. The characteristics of leptin secretion are complex
and fundamentally different from those of CCK. Leptin
secretion in adults displays a prominent circadian rhythm
and is not affected by individual meals [76]. Fig. 5 shows
this circadian rhythm of plasma leptin levels and the lack of
influence of meals. In addition, plasma leptin concentration
is positively correlated with body adiposity. As shown in
Fig. 6, the relationships between body adiposity and morning fasting plasma leptin concentrations levels are linear in
adult men and women, but leptin concentrations are two–
three times higher in women than in men and are affected by
the hypothalamic –pituitary –gonadal axis function in women [74]. Finally, leptin secretion drops markedly during
fasting, possibly disinhibiting eating.
3.2. Receptors
Although leptin receptors are widespread in the body,
local-infusion experiments indicate that the populations of
leptin receptors that mediate its effects on eating are in the
brain, in the arcuate nucleus of the hypothalamus and in the
Fig. 5. Circadian rhythms of (top panel) serum leptin concentration
(expressed as percent change from the 0800-h fasting level of 12.0 F 4.4
ng/ml), (middle panel) insulin (AU/ml), and (bottom panel) glucose (mg/dl).
Note that meals, indicated by arrows in the x axis of the bottom panel,
clearly affect insulin and glucose concentrations but do not affect leptin
concentration. Data are from normal-weight men and women. The leptin
pattern shown was similar in obese participants (BMI 38.8 F 2.5 kg/m2),
but the 0800-h leptin level was significantly elevated (41.7 F 9.0 ng/ml).
From Ref. [76], used with permission.
Fig. 6. Linear relationships between plasma leptin concentration (ng/ml)
and body fat mass (kg, measured by hydrodensitometry) in men (aged 19 –
41 years) and premenopausal (aged 19 – 45 years) and postmenopausal
women (aged 49 – 87 years). Regression coefficients were .99, .95, and .92
in the three groups, respectively (all Ps < .0001). From Ref. [74], used with
permission.
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dorsal vagal complex [27,36]. This localization complicates
normal endocrine function: Leptin must pass through the
blood – brain barrier to reach these receptors, which it does
via a selective active transport mechanism [7].
3.3. Physiological dose
In his authoritative review of the physiology of leptin,
Friedman [27] cites two data sets to support the claim that
physiological doses of leptin are sufficient to affect eating.
Neither is convincing. The first data set is a comparison of
one experiment demonstrating that plasma leptin levels
increase in mice in which body weight increase are induced
by feeding chow enriched with 10% or 45% fat [88] with
another experiment demonstrating that continuous subcutaneous leptin infusions, in doses that produce leptin levels in
the same range as high-fat feeding does, decreased body
weight [38]. There are several limitations to the interpretation of this comparison. (1) Only body weight, not food
intake, was measured, and the degree to which the weight
loss mirrored hypophagia is unclear. Indeed, the authors
reported increases in energy expenditure that may have
accounted for much of the weight change. (2) Due to the
changes in leptin transport and postreceptor function, leptin
is much more potent in lean or underweight mice than in
overweight, fat-fed mice. This is known as leptin resistance.
The implication here is that the comparison is between
essentially different animals. That is, there is no evidence
that the elevated endogenous leptin levels in the overweight
mice affected eating in them, and these levels can be
considered pharmacological in the lean mice because they
never occur in them. (3) The association between plasma
leptin level and weight loss was not close, especially in the
lower ranges of leptin concentration, and not statistically
substantiated. In sum, these data are no more than encouraging. In the second data set, rats’ leptin levels were
monitored over 14 days, during which they received chronic
subcutaneous control or leptin infusions by osmotic minipump [2]. Although control rats progressively increased
daily food intake and increased body weight about 80 g,
their plasma leptin levels remained constant throughout the
experiment, at about 4 ng/ml diurnally and 2.5 ng/kg
nocturnally. Infusion of 2 or 4 Ag/h leptin produced doserelated decreases in food intake and weight gain. Plasma
leptin levels during the infusions, however, were 5– 7 ng/ml
diurnally and 4 – 7 ng/ml nocturnally for the two doses,
which is more than the endogenous levels measured at any
time in control rats. Thus, these data provide no direct
evidence for the physiological dose criterion for leptin’s
satiating effect. The fact that leptin infusions that produced
only mild pharmacological levels of plasma leptin in rats
was considered encouraging because obese rats have been
reported to display such leptin levels. This comparison is
subject to the complications discussed above.
There are several indications that leptin’s physiological
role may be to disinhibit eating (and inhibit energy expen-
diture) when body adiposity is low rather than to inhibit
eating (and stimulate energy expenditure) when adiposity is
high [1,48,75]. Rosenbaum et al. [73] recently devised an
elegant experiment to test the physiological status of leptin
in this context. Several indices of energy expenditure were
measured in participants at their usual body weight, while
stable at 90% usual weight, and during a 5-week period at
90% usual weight during which they received twice-daily
leptin injections that restored leptin concentration measured
at 0800 h to the level at usual body weight. Normalizing
leptin levels while the participants were at 90% of their
usual weight reversed the decreases in plasma T3 and T4
levels and in nonresting energy expenditure that, otherwise,
were caused by weight loss. These data suggest that the
inhibitory effect on energy expenditure of decreased leptin
levels meets the physiological dose criterion in humans. It
would be fascinating to learn the effects of this or a similar
chronic regimen on eating behavior in humans or animals.
Such results would certainly have much more import than
will the commonly used strategy of infusing leptin in rats
following 2 – 4 days of total starvation.
3.4. Removal and replacement
Although the extirpation of the leptin-secreting cells, i.e.,
the adipocytes, is possible, this has not been done in the
context of a test of leptin on eating. Nor, of course, would the
removal of the adipose tissue result in a selective loss of
leptin. Genetic models of leptin removal are more interesting. Obese (ob/ob) and diabetic (db/db) mice display identical syndromes of increased meal size, hyperphagia, obesity,
and diabetes. It is now known that these syndromes arise
from disruptions of leptin signaling: the wild-type ob gene,
lep, encodes leptin, and the wild-type db gene, lep-r, encodes
the leptin receptor [1,27,48]. Classic studies of the parabiosis
of normal, ob/ob, and db/db mice [16] had indicated that
these animals had a defective hormone and hormone receptor, respectively, long before either was identified. Leptin
infusion has also been shown to reverse the hyperphagia and
obesity of ob/ob mice [27,38]. In addition, transgenic reconstitution of lep-r in db/db mice ameliorates their hyperphagia
and obesity [46]. Humans with two defective lep genes and a
phenotype analogous to that of the ob/ob mouse have been
identified, and chronic leptin treatment has been shown to
ameliorate their syndrome [24,68].
These data from mice and humans support the removal
and replacement criterion for physiological hormonal action.
They are not, however, definitive evidence. As discussed
above (see CCK), most signaling molecules, including
leptin, are synthesized in sites other than the site of interest
for the hormonal action in question. Hence, the phenotypes
of interest in individuals with null mutations may arise from
the effects of the molecule other that the hypothesized effect.
Other limitations of such data are that (1) null mutations
prevent any hormone secretion, not just the particular aspect
of secretion relevant to the hypothesized effect; (2) null
N. Geary / Physiology & Behavior 81 (2004) 719–733
mutations can produce pathophysiological effects beginning
at any time in development when the gene is normally
expressed, including effects unrelated to the hormonal action
in question; and (3) such chronic developmental effects can
produce compensatory physiological responses. Thus, in
several respects, the adult organism bearing a null mutation
falls far short of an ideal test, in which a hormone is suddenly
removed, and cannot be considered crucial data. Many of
these problems will be averted by the development of acutely
inducible, tissue-specific gene knockouts and knock-ins,
which will lead to more compelling evidence.
3.5. Antagonism
Effective leptin receptor antagonists have not yet been
developed. A test of leptin antagonism on eating, using a
passive immunization strategy, has been reported [15]. Food
intake increased about 25% in normal rats in the 20 h following an intracerebroventricular injection of rabbit antimouse
leptin antibodies; there was no effect on eating in Zucker fa/fa
rats, which have defective leptin receptors (Fig. 7). The
antibodies’ effect on exogenous leptin’s satiating action
was not tested. These data provide support for one aspect
of the antagonism criterion, but they are not proof because (1)
there remains a question as to how an intracerebroventricularly injected antibody reaches the brain parenchyma and (2)
the interpretation of acute tests of what may be a tonic
physiological signal raises caveats, which are discussed
below.
Fig. 7. Intracerebroventricular injection of rabbit antimouse leptin antibodies
increases food intake in rats. Filled symbols are cumulative food intake after
injection with 10 Al preimmune IgG, and open symbols are cumulative food
intakes following injection of 10 Al antileptin IgG (mean F S.E.M.). This
dose of leptin antibodies has an in vitro binding capacity of about 1 ng rat
leptin. The number of rats tested in each condition is represented by n.
* Significant difference. From Ref. [15], used with permission.
727
3.6. Formulation: leptin may be uncoupled endocrine
satiation signal
Leptin research has catalyzed a revolution in behavioral
neuroscience, especially regarding the genetic and hypothalamic mechanisms of eating. Despite this progress, however,
the hypothesis that satiation is a normal hormonal effect of
leptin remains unproven and suspect. Leptin satiation has
not yet fulfilled several classical endocrine criteria for a
physiological effect, notably the crucial physiological dose
and antagonism criteria. Further work is required to better
substantiate this hypothesis.
Many of the controls of leptin secretion, including
circadian changes and changes during fasting, are not well
understood. Furthermore, neither the temporal linkage nor
the mediating mechanisms between any parameter of the
pattern of leptin secretion and satiation during individual
meals are understood. Leptin’s hypothetical satiation effect,
therefore, appears fully uncoupled (Fig. 4).
The uncoupled nature of leptin signaling greatly
complicates the evaluation of the endocrine criteria for
physiological function. What, in the complex pattern of
leptin secretion, is the effective stimulus for satiationmaximum nocturnal or diurnal plasma level, the level at
some specific time of day, the average level over the
day, or some other parameter? How long after a change
in endogenous leptin does eating change? Do the effects
of a single bolus injection of leptin have any physiological relevance? These are difficult questions. Their
answers will determine how and when leptin should be
administered and when eating should be measured to
best test the physiological dose criterion for this hormone
(as well as to optimize leptin’s pharmacotherapeutic use).
It may be that slow infusion is the ideal way to test
leptin’s effects, but this creates its own problems. For
example, chronic leptin administration can lead to dynamic responses that cloud interpretation. When recombinant human leptin was administered by daily
subcutaneous injections to obese human participants for
nearly 6 months, it required 10- to 40-fold elevations of
plasma leptin to produce significant weight loss, and this
insensitivity was, in part, due to the neutralization of
leptin’s biological activity by the development of antibodies in the majority of participants [41]. The administration of leptin to leptin-deficient humans also led to
the production of antibodies [68]. At this point, effective
strategies to avoid such difficulties have not been developed either in experimental physiology or pharmacological therapeutics.
4. Ghrelin
Ghrelin robustly stimulates eating, suggesting the hypothesis that ghrelin is a fully coupled signal for hunger
and meal initiation [85,92,93]. In addition, basal ghrelin
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N. Geary / Physiology & Behavior 81 (2004) 719–733
secretion is affected by body adiposity, suggesting that
ghrelin also may have an uncoupled hunger effect. Whether
ghrelin affects spontaneous eating solely by increasing
meal frequency, as these hypotheses predict, however, is
not yet known.
4.1. Secretion
Ghrelin is synthesized and released primarily by endocrine cells in the stomach. Although the specific stimuli for
ghrelin secretion are unknown, the increases in plasma
concentration of ghrelin before meals and rapid decreases
after meals are consistent with a hunger-inducing action in
both humans and rats [18,86]. However, plasma ghrelin
concentration in humans also increases during the evening
and decreases in the early morning hours, in the absence of
eating, [19] suggesting that ghrelin is not sufficient for a
secretion-coupled hunger effect. Basal ghrelin levels are
also decreased in obese humans and increased by weight
loss [19,87], suggesting that this hormone may also be
linked to the control of eating by adiposity. The circadian
pattern of plasma ghrelin concentrations in humans is shown
in Fig. 8. Ghrelin is also synthesized in neurons in the
arcuate nucleus of the hypothalamus; thus, the molecule
may also have central, nonendocrine actions on eating [17].
4.2. Receptors
Ghrelin was originally identified as the endogenous ligand
for the pituitary growth hormone secretogogue receptor [44].
Local injection studies suggest that ghrelin receptors in the
paraventricular and arcuate nuclei of the hypothalamus mediate its eating effect [5,67,93]. Ghrelin is transported across
the blood –brain barrier [8], but whether the primary ligand
for hypothalamic ghrelin receptors is hormonal ghrelin or
ghrelin released by neurons projecting from the arcuate
nucleus remains unclear. The arcuate nucleus, however, is
not the only site where ghrelin may act to stimulate eating.
Similar to leptin [36], there are ghrelin receptors in the
brainstem, and ghrelin injection into the dorsal vagal complex
stimulates eating. Furthermore, ghrelin receptors also exist in
abdominal vagal afferent neurons, and abdominal vagotomy
or capsaicin deafferentation eliminated the effect of intravenous infusions of ghrelin on eating, suggesting that these
peripheral ghrelin receptors mediate the endocrine hunger
effect of ghrelin [20]. Some of these data are shown in Fig. 9.
4.3. Physiological dose
This criterion has been addressed so far only in a study
by Wren et al. [92]. In normal-weight men and women,
Fig. 8. Circadian rhythms of plasma ghrelin (pg/ml) in men and women before (BMI 35.6F1.6 kg/m2) and after (BMI 29.4F1.5 kg/m2) diet-induced
weight loss. Note that (1) ghrelin levels increase progressively prior to meals and decrease after meals, (2) ghrelin also increases during the evening
before decreasing during the early morning hours, and (3) ghrelin levels are greater in normal-weight than in obese participants. From Ref. [19], used
with permission.
729
N. Geary / Physiology & Behavior 81 (2004) 719–733
4.4. Removal and replacement
There is some evidence that ghrelin meets this criterion.
Cummings et al. [19] showed that plasma ghrelin concentrations were maintained at a very low, constant level in
obese patients who had had proximal Roux-en-Y gastric
bypass surgery (Fig. 8), and patients who undergo gastric
bypass have been reported to be hungry less often and eat
fewer meals than they had prior to surgery [39]. Of course,
it is also possible that such changes in eating are due to
alterations in the actions of ingested food at postgastric
sites following gastric bypass rather than to reduced
ghrelin.
A transgenic animal lacking ghrelin has also been
constructed [84]. Extensive efforts to demonstrate a phenotype of decreased eating in this animal met with no
success. Although these data do not encourage the view
that ghrelin is a necessary signal for eating, the same
caveats that limit the interpretation of the positive effects
of mutations of the CCK and leptin signaling systems
prevent these negative data from being a crucial test of
the ghrelin hunger hypothesis.
4.5. Antagonism
Fig. 9. Surgical abdominal vagotomy (top panel) and abdominal deafferentation by perivagal capsaicin injection (bottom panel) each block the
stimulatory effect on eating of intravenously infused ghrelin in rats.
Controls are intact rats; open bars are saline injections; filled bars are
ghrelin injections. These vagal lesions had no effect on the stimulatory
effect of intracerebroventriculalry administered ghrelin (data not shown).
* Significant difference. From Ref. [20], used with permission.
intravenous infusion of 5 pMol/kg/min human ghrelin
increased hunger ratings and meal size (Table 3). These
infusions increased plasma ghrelin concentrations about
2.5-fold over the fasting level, indicating that the infusions
were out of the physiological range. Indeed, the aphysiological nature of the infusions is indicated by the fact that
the participants perceived that hunger did not decrease even
after their large lunches. Thus, more work is required to
determine if ghrelin meets this criterion for a fully coupled
physiological hormonal effect.
Chronic subcutaneous or intracerebroventricular administration of ghrelin has been shown to increase eating and
body weight in mice and rats [65,86], but no efforts have yet
been made to determine if physiological doses are sufficient
for these potential secretion-uncoupled effects. A major
issue that requires clarification in this context is that ghrelin
often seems to stimulate energy metabolism and increase
body weight more rapidly and more potently than it affects
eating [86].
There are at least four reports that ghrelin antagonism
reduces eating. Intracerebroventicular injections of ghrelin
antibodies decreased eating both acutely (i.e., 1- or 2h food intake measures in rats refed after fasting) and
chronically (i.e., during a day or two following injection;
[5,64,65]). Some of these data are shown in Fig. 10. The
effect of intravenous infusion of ghrelin antibodies, however, has not been tested as yet. As antibodies do not
penetrate the blood – brain barrier, such an experiment has
the potential to differentiate hormonal and neural ghrelin
as the source of the ghrelin blocked by intracerebroventricular ghrelin antibody injection. Intracerebroventricular
injections of a peptide ghrelin receptor antagonist both
decreased eating and blocked the acute stimulatory effect
of intraperitoneally injected ghrelin on eating [4]. This
same antagonist also decreased eating when injected
intraperitoneally, but whether the site of action was
peripheral or central was not established. Taken together,
Table 3
Intravenous infusion of ghrelin increase hunger and meal size in normalweight men and women
Saline
Ghrelin
Plasma ghrelin (nMol/l)
Hunger (cm)
Meal size (kJ)
2.5 F 0.5
5.9 F 0.3a
5.8 F 0.8
6.9 F 0.7a
4713 F 344
5997 F 413a
Participants were five men and four women (BMI 23 F 1 kg/m2). Infusions
of saline or 5 pMol/kg/min human ghrelin were begun at 0830 h.
Participants ate a fixed breakfast (1550 kJ) at 1030 h and were offered a
buffet lunch at 1230 h. Data (mean F S.E.M.) are plasma ghrelin level
measured just before lunch, hunger rated on a 10-cm visual analog scale
just before lunch, and lunch size.
a
Significantly different from saline. Data are from Ref. [92].
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N. Geary / Physiology & Behavior 81 (2004) 719–733
5. Discussion
Fig. 10. Intracerebroventricular injection of rabbit antirat ghrelin antibodies
decreases food intake in rats. Open bars are food intake after injection with
10 Al preimmune IgG, and closed bars are intakes following injection of
10 Al antighrelin IgG (mean F S.E.M.). Top panel: 2-h food intakes in rats
tested after an 8-h fast. Bottom panel: 12-h dark-phase food intakes in freefeeding rats injected at the beginning of the dark. * Significant decrease in
food intake, P < .005, * * P < .001. From Ref. [65], used with permission.
Eating is a complex function of the brain that has been
profitably analyzed from a number of scientific perspectives, including psychological, nutritional, neuroanatomical,
neurochemical, electrophysiological, endocrinological, and,
most recently, molecular genetic perspectives (see Refs.
[11,32] for synthetic overviews). Endocrine signals have
emerged as an especially important aspect of the physiology
of eating. In the analysis of these signals, it is of vital
importance to capitalize on the critical tools of classical
endocrinology. Failure to do so precludes establishing the
true physiological nature of endocrine signals, leaving the
rest of the research edifice built around them without a
reliable foundation. This review has attempted to crystallize
some methodogical and interpretive guidelines for the
application of classic endocrine criteria for establishing a
physiological effect of a hormone using the examples of
three hypothesized endocrine controls of eating, CCK,
leptin, and ghrelin.
The endocrine criteria for a physiological hormonal
effect (Table 1) are stringent, and fulfilling them to the level
of scientific certainty is a formidable task. At present, of the
many hypothesized endocrine controls of eating ([90] and
Table 4), CCK’s satiating effect in humans comes closest to
fulfilling these criteria. The physiological statuses of other
hormonal eating signals are best considered, more or less,
open questions that require further research. It is appropriate
to emphasize that these criteria address only the endocrine
function of these hormones up to and including binding to
their cognate receptors. The criteria, and this review, have
not considered the physiological mechanisms activated
consequent to hormone receptor activation, in particular,
the altered peripheral and central neural information processing. It is important to note that progress in analyzing
postreceptor mechanisms mediating endocrine controls of
eating does not necessarily parallel progress in analyzing
these data suggest that both forms of the ghrelin hunger
hypothesis may meet the antagonism criterion.
Table 4
Hypothesized endocrine controls of eating
4.6. Formulation: ghrelin may have both coupled and
uncoupled endocrine satiation effects
The investigation of the role of ghrelin in hunger is in early
days. Initial data encourage the hypotheses that preprandial
ghrelin secretion may be a fully coupled endocrine hunger
signal and that basal ghrelin may be a partially or fully
uncoupled hunger signal. As yet, however, none of the
criteria for a physiological endocrine effect has been fully
met for either hypothesis. The research programs described
above for the endocrine effects of CCK and leptin should help
inform work on ghrelin. As in the other cases, however, this
peptide presents has its own special difficulties, such as the
relative effect of hormonal ghrelin and of neuronal ghrelin.
Inhibitory
Excitatory
CCK
Leptin
Ghrelin
Pancreatic glucagon
Insulin
Amylin
Apoliprotein A-IV
Gastrin-releasing peptide
Neuromedin B
Somatostatin
Neurotensin
Glucagon-like peptide 1
Glucagon-like peptide 2
Peptide YY(3-36)
Enterostatin
Estradiol
Ghrelin
Testosterone
N. Geary / Physiology & Behavior 81 (2004) 719–733
their peripheral endocrine aspects. The substantial progress
on the molecular genetic and neural mechanisms of leptin
and ghrelin signaling, e.g., encourages further research into
their roles in eating independent of their present status as
endocrine controls. Ultimately, however, all these aspects of
the molecule’s function must be explicitly tied to a proven
endocrine effect on eating or must be considered either
nonendocrine or nonphysiological effects.
This review developed the concepts of coupled and
uncoupled hormonal effects. As discussed above, a fully
coupled endocrine control is characterized by two apparently time-locked causal physiological cascades, the first linking a specific food stimulus with altered hormone secretion
and the second linking the hormonal change with a specific
change in eating, e.g., meal initiation or termination (Fig. 4,
upper panel). CCK apparently exemplifies fully coupled
endocrine control. In contrast, an endocrine effect is fully
uncoupled when neither the stimuli controlling the hormone
secretion nor the temporal linkage or mediating mechanisms
between hormone secretion and changed eating is clearly
established (Fig. 4, lower panel). If only one of these two
links appears coupled, the endocrine effect may be called
partially coupled.
The distinction between coupled and uncoupled hormonal effects emphasizes differences in the putative causal
relationships between endocrine function and eating. Each
of the endocrine controls of eating considered here is also a
feedback control, in that hormone secretion is tied, directly
or indirectly, to past eating behavior. This is not the crux of
the coupling concept, however, and not all endocrine controls are feedback controls [29].
The chief advantage of the coupling concept is that it
provides concrete empirical approaches and interpretative
criteria applicable to a large number of endocrine controls of
eating, as exemplified in the previous discussions. The
coupling concept is distinct from, and complements and
extends, previous concepts that have been applied to endocrine controls of eating, such as phasic and tonic effects
[28], direct and indirect effects [77], and meal and adiposity
signals [91]. For example, the direct and indirect controls of
meal size of Smith [77] relate only to satiation and are not
restricted to endocrine mechanisms. Similarly, although the
hypothesized uncoupled effects of leptin and ghrelin meet
the criteria for adiposity signals [91], other endocrine effects
that are not adiposity signals, such as endocrine signals
affected by metabolism or reproductive function [28 – 30],
also fit the uncoupled concept. Thus, the scheme of coupled
and uncoupled endocrine effects on eating may provide a
new and useful conceptual framework for the study of
eating.
Acknowledgements
The author is supported by NIH research grants
DK54523, AA526403, and MH529977.
731
References
[1] Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends
Endocrinol Metab 2000;11:327 – 32.
[2] Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct physiologic and
neuronal responses to decreased leptin and mild hyperleptinemia.
Endocrinology 1999;140:4923 – 31.
[3] Antin J, Gibbs J, Holt J, Young RC, Smith GP. Cholecystokinin elicits
the complete behavioral sequence of satiety in rats. J Comp Physiol
Psychol 1975;89:784 – 90.
[4] Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA,
et al. Antagonism of ghrelin receptor reduces food intake and body
weight gain in mice. Gut 2003;52:947 – 52.
[5] Bagnasco M, Tulipano G, Melis MR, Argiolas A, Cocchi D, Muller
EE. Endogenous ghrelin is an orexigenic peptide acting in the arcuate
nucleus in response to fasting. Regul Pept 2003;111:161 – 7.
[6] Ballinger A, McLoughlin L, Medbank S, Clark M. Cholecystokinin is
a satiety hormone in humans at physiological post-prandial concentrations. Clin Sci 1995;89:375 – 81.
[7] Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin
enters the brain by a saturable system independent of insulin. Peptides
1996;17:305 – 11.
[8] Banks WA, Tschöpp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood – brain barrier is determined by
its unique primary structure. J Pharmacol Exp Ther 2002;102:823 – 7.
[9] Barrington EJW. An introduction to general and comparative endocrinology. Oxford: Clarendon Press; 1963. p. 33 – 5.
[10] Beglinger C, Degen L, Matzinger D, D’Amato M, Drewe J. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and
hunger feedings in humans. Am J Physiol 2001;280:R1149 – 54.
[11] Berthoud HR. Multiple neural systems controlling food intake and
body weight. Neurosci Biobehav Rev 2002;26:393 – 428.
[12] Bi S, Moran TH. Actions of CCK in the controls of food intake and
body weight: lessons from the CCK-A receptor deficient OLETF rat.
Neuropeptides 2002;36:171 – 81.
[13] Blundell J. Pharmacological approaches to appetite suppression.
Trends Pharmacol Sci 1991;12:147 – 57.
[14] Brenner L, Yox DP, Ritter RC. Suppression of sham feeding by intraintestinal nutrients is not correlated with plasma cholecystokinin elevation. Am J Physiol 1993;264:R972 – 6.
[15] Brunner L, Nick H-P, Cumin F, Chiesi M, Baum H-P, Whitebread S, et
al. Leptin is a physiologically important regulator of food intake. Int J
Obes 1997;21:1152 – 60.
[16] Coleman DL. Obese and diabetes: two mutant genes causing diabetesobesity syndromes in mice. Diabetologia 1978;14:141 – 8.
[17] Cowley MA, Smith RG, Diano S, Tschöpp M, Pronchuk N, Grove
KL, et al. The distribution and mechanism of action of ghrelin in the
CNS demonstrates a novel hypothalamic circuit regulating energy
homeostasis. Neuron 2003;37:649 – 61.
[18] Cox JE. Cholecystokinin satiety involves CCKA receptors perfused
by the superior pancreaticoduodenal artery. Am J Physiol 1998;
274:R1390 – 6.
[19] Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger
EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric
bypass surgery. N Engl J Med 2002;346:1623 – 30.
[20] Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H,
et al. The role of the gastric afferent vagal nerve in ghrelin-induced
feeding and growth hormone secretion in rats. Gastroenterology 2002;
123:1120 – 8.
[21] Dourish CT, Ruckert AC, Tattersall FD, Iversen SD. Evidence that
decreased feeding by systemic injection of cholecystokinin is mediated by CCK-A receptors. Eur J Pharmacol 1989;173:233 – 4.
[22] Doyle JW, Wolfe MM, McGuigan JE. Hepatic clearance of gastrin and
cholecystokinin peptides. Gastroenterology 1984;87:60 – 8.
[23] Eckel LA, Langhans W, Kahler A, Campfield LA, Smith FJ, Geary N.
Chronic administration of OB protein decreases food intake by selec-
732
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
N. Geary / Physiology & Behavior 81 (2004) 719–733
tively reducing meal size in female rats. Am J Physiol 1998;275:
R186 – 93.
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with
congenital leptin deficiency. N Engl J Med 1999;341:879 – 84.
Flynn MC, Scott TR, Pritchard TC, Plata-Salaman CR. Mode of
action of OB protein (leptin) on feeding. Am J Physiol 1998;275:
R174 – 9.
Fried M, Mayer EA, Jansen JBMJ, Lamers CBHW, Taylor H, Bloom
SR. Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal. Gastroenterology
1988;95:1344 – 50.
Friedman JM. Leptin and the regulation of body weight. Harvey Lect
Ser 2001;95:107 – 36.
Geary N. Estradiol, CCK and satiation. Peptides 2001;22:1251 – 63.
Geary N. Hunger and satiation. In: Martini L, editor. Encyclopedia of endocrine diseases. San Diego (CA): Academic Press; 2004
[in press].
Geary N. The estrogenic inhibition of eating. In: Stricker E, Woods
SC, editors. Handbook of behavioral neuroscience. 2nd ed. New York:
Kluwer Academic Publishing; 2004. p. 305 – 43.
Geary N, Kissileff HR, Pi-Sunyer FX, Hinton V. Individual, but not
simultaneous, glucagon and cholecystokinin infusions inhibit feeding
in men. Am J Physiol 1992;262:R975 – 80.
Geary N, Schwartz GJ. Appetite. In: Sadock BJ, Sadock VA, editors.
6th ed. Comprehensive Textbook of Psychiatry, vol. 1. Baltimore:
Williams and Wilkins; 2004 [in press].
Gibbs J, Young RC, Smith GP. Cholecystokinin elicits satiety in rats
with open gastric fistulas. Nature 1973;245:323 – 5.
Greenberg D, Smith GP, Gibbs J. Infusion of CCK-8 into the hepatic
portal vein fails to reduce food intake in rats. Am J Physiol 1987;252:
R1015 – 8.
Griffin JE, Ojeda SR. Textbook of endocrine physiology. 4th ed. New
York: Oxford Univ. Press; 2000.
Grill HJ, Kaplan JM. The neuroanatomical axis for the control of
energy balance. Front Neuroendocrinol 2002;23:2 – 40.
Grossman MI. Chemical messengers: a view from the gut. Fed Proc
1979;38:2341 – 3.
Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central
leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A
1997;94:8878 – 83.
Halmi KA, Mason E, Falk JR, Stunkard A. Appetitive behavior after
gastric bypass for obesity. Int J Obes 1981;5:457 – 64.
Hewson G, Leighton GE, Hill RG, Hughes J. The cholecystokinin
receptor antagonist L364,718 increases food intake in the rat by
attenuation of the action of endogenous cholecystokinin. Br J Pharmacol 1988;93:79 – 84.
Heymsfeld SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R,
Hunt T, et al. Recombinant leptin for weight loss in obese and lean
adults. J A Med Assoc 1999;282:1568 – 75.
Kahler A, Geary N, Eckel LA, Campfield LA, Smith FJ, Langhans W.
Chronic administration of OB protein decreases spontaneous food
intake by reducing meal size in male rats. Am J Physiol 1998;275:
R180 – 6.
Kissileff HR, Carrettta JC, Geliebter A, Pi-Sunyer FX. Cholecystokinin and stomach distension combine to reduce food intake. Am J
Physiol 2003;285:R992 – 8.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.
Ghrelin is a growth-hormone releasing acylated peptide from stomach.
Nature 1999;402:656 – 60.
Kopin AS, Mathes WF, McBride EW, Nguyen M, Al-Haider W,
Schmitz F, et al. The cholecystokinin—a receptor mediates inhibition
of food intake yet is not essential for the maintenance of body weight.
J Clin Invest 1999;103:383 – 91.
Kowalski TJ, Liu SM, Leibel RL, Chua Jr SC. Transgenic complementation of leptin-receptor deficiency: I. Rescue of the obesity/dia-
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
betes phenotype of LEPR-null mice expressing a LEPR-B transgene.
Diabetes 2001;50:425 – 35.
Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology. 10th ed. Philadelphia (PA): Saunders; 2003.
Leibel RL. The role of leptin in the control of body weight. Nutr Rev
2002;60:S15 – 9.
Liddle RA. Cholecystokinin. In: Walsh JH, Dockray GJ, editors. Gut
peptides: physiology and biochemistry. New York: Raven Press; 1994.
p. 175 – 216.
Liddle RA. Cholecystokinin cells. Annu Rev Physiol 1997;59:221 – 42.
Liddle RA, Gertz BJ, Kanayama S, Beccaria L, Coker LD, Turnbill
TA, et al. Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in
humans. J Clin Invest 1989;84:1220 – 5.
Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA. Cholecystokinin bioactivity in human plasma. J Clin Invest 1985;75:
1144 – 52.
Lieverse RJ, Jansen JMB, van de Zwan A, Samson L, Masclee AM,
Lamers CBHW. Effects of a physiological dose of cholecystokinin on
food intake and postprandial satiation in humans. Regul Pept 1993;
43:83 – 9.
Lieverse RJ, Jansen JMB, Masclee AAM, Lamers CBHW. Satiety
effects of a physiological dose of cholecystokinin in humans. Gut
1995;36:176 – 9.
Marchal-Victorion S, Vionnet N, Escrieut C, Dematos F, Dina C,
Dufresne M, et al. Genetic, pharmacological and functional analysis
of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in
type 2 diabetes and obese patients. Pharmacogenetics 2002;12:23 – 30.
Mamoun AH, Bergström J, Södersten P. Cholecystoknin octapeptide
inhibits carbohydrate but not protein intake. Am J Physiol 273:
R972 – 80.
Matzinger D, Gutzwiller J.-P., Drewe J, Orban A, Engel R, D’Amato
M, et al. Inhibition of food intake in response to intestinal lipid is
mediated by cholecystokinin in humans. Am J Physiol 1999;277:
R1718 – 24.
Medvei VC. A history of endocrinology. Lancaster (UK): MTP Press;
1982.
Miller LJ, Holicky EL, Ulrich CD, Wieben ED. Abnormal processing
of the human cholecystokinin receptor gene in association with gallstones and obesity. Gastroenterology 1995;109:1375 – 80.
Moran TH, Ameglio PJ, Schwartz GJ, McHugh PR. Blockade of type
A, not type B, CCK receptors attenuates satiety actions of exogenous
and endogenous CCK. Am J Physiol 1992;262:R46 – 50.
Moran TH, Katz LF, Plata-Salaman CR, Schwartz GJ. Disordered
food intake and obesity in rats lacking cholecystokinin A receptors.
Am J Physiol 1998;274:R618 – 25.
Moran TH, Ladenheim EE. Identification of receptor populations mediating the satiating actions of brain and gut peptides. In: Smith GP,
editor. Satiation from gut to brain. New York: Oxford Univ. Press;
1998. p. 126 – 63.
Moran TH, Robinson PH, Goldrich MS, McHugh PR. Two brain
cholecystokinin receptors: implications for behavioral actions. Brain
Res 1986;362:175 – 9.
Murakami N, Hayashida T, Kuroiwa T, Nakahara K, Ida T, Mondal
MS, et al. Role for ghrelin in food intake and secretion profile of
stomach ghrelin in rats. J Endocrinol 2002;174:283 – 8.
Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa
K, et al. A role for ghrelin in the central regulation of feeding. Nature
2001;409:194 – 8.
Nolan LJ, Guss JL, Liddle RA, Pi-Sunyer FX, Kissileff HR. Elevated
plasma cholecystoknin and appetitive ratings after consumption of a
liquid meal in humans. Nutrition 2003;19:553 – 7.
Olszewski PK, Grace MK, Billington CJ, Levine AS. Hypothalamic
paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides 2003;24:919 – 23.
O’Rahilly S, Farooqi IS, Yeo GS, Challis BG. Minireview: human
N. Geary / Physiology & Behavior 81 (2004) 719–733
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
obesity—lessons from monogenic disorders. Endocrinology 2003;
144:3757 – 64.
Reidelberger RD, Kalogeris TJ, Solomon TE. Comparative effects of
caerulein on food intake and pancreatic secretion in dogs. Brain Res
Bull 1986;17:445 – 9.
Reidelberger RD, O’Rourke MF. Potent cholecystokinin antagonist L364,718 stimulates food intake in rats. Am J Physiol 1989;257:
R1215 – 8.
Reidelberger RD, Solomon TE. Comparative effects of CCK-8 on
feeding, sham feeding, and exocrine pancreatic secretion in rats.
Am J Physiol 1986;251:R97 – 105.
Reidelberger RD, Varga G, Liehr RM. Cholecystokinin suppresses
food intake by a nonendocrine mechanism in rats. Am J Physiol
1994;267:R901 – 4.
Rosenbaum M, Murphy EM, Heymsfeld SB, Matthews DE, Leibel RL.
Low dose leptin administration reverses effects of sustained weightreduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab 2002;87:2391 – 4.
Rosenbaum M, Nicholson M, Hirsch J, Heymsfield SB, Gallagher D,
Chu F, et al. Effects of gender, body composition, and menopause on
plasma concentration of leptin. J Clin Endocrinol Metab 1996;81:
3424 – 7.
Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel
RL. Is the energy homeostasis system inherently biased toward weight
gain? Diabetes 2003;52:232 – 8.
Sinha MK, Channesian JP, Heiman ML, Kriauciunas A, Stephens TW,
Magosin S, et al. Nocturnal rise of leptin in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J Clin Invest 1996;
97:1344 – 7.
Smith GP. The direct and indirect controls of meal size. Neurosci
Biobehav Rev 1996;20:41 – 6.
Smith GP. Introduction. In: Smith GP, editor. Satiation from gut to
brain. New York: Oxford Univ. Press; 1998. p. 3 – 9.
Smith GP. Cholecystokinin—the first twenty-five years. In: Bray GA,
Ryan DH, editors. Nutrition, genetics and obesity. Pennington Center
Nutrition Series, vol. 9. Baton Rouge (LA): State Univ. Press; 1999.
p. 227 – 45.
Smith GP, Gibbs J. The development and proof of the CCK hypothesis of satiety. In: Dourish CT, Cooper SJ, Iversen SD, Iversen LL,
editors. Multiple cholecystokinin receptors in the CNS. New York:
Oxford Univ. Press; 1992. p. 166 – 82.
733
[81] Smith GP, Gibbs J. The satiating effects of cholecystokinin and bombesin-like peptides. In: Smith GP, editor. Satiation from gut to brain.
New York: Oxford Univ. Press; 1998. p. 97 – 125.
[82] Smith GP, Tyrka A, Gibbs J. Type-A CCK receptors mediate the
inhibition of food intake and activity by CCK in 9- to 12-day old
rat pups. Pharmacol Biochem Behav 1991;38:207 – 10.
[83] Strubbe JH, Wolsink JG, Schutte AM, Prins AJA. Hepatic-portal and
cardiac infusion of CCK-8 and glucagon induce different effects on
feeding. Physiol Behav 1989;46:643 – 6.
[84] Sun Y, Ahmed S, Smith RO. Deletion of ghrelin impairs neither
growth nor appetite. Mol Cell Biol 2003;23:7973 – 81.
[85] Tolle V, Bassant M.-H., Zizzari P, Poindessous-Jazat F, Tomasetto C,
Epelbaum J, et al. Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep – wake patterns in rats.
Endocrinology 2002;143:1353 – 61.
[86] Tschöpp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in
rodents. Nature 2000;407:908 – 13.
[87] Tschöpp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin ER,
Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707 – 9.
[88] Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, et al. Diet-induced obese mice develop peripheral, but not
central, resistance to leptin. J Clin Invest 1997;99:385 – 90.
[89] West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses
meal size but not food intake in free-feeding rats. Am J Physiol
1984;246:R776 – 87.
[90] Woods SC. Gastrointestinal satiety signals: I. An overview of gastrointestinal signals that influence food intake. Am J Physiol 2004;
286:G7 – 13.
[91] Woods SC, Schwartz MW, Baskin DG, Seeley RJ. Food intake and
the regulation of body weight. Annu Rev Psychol 2000;51:255 – 77.
[92] Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG,
et al. Ghrelin enhances appetite and increases food intake in humans.
J Clin Endocrinol Metab 2001;86:5992 – 5.
[93] Wren AM, Small CJ, Abbot CR, Dhillo WS, Seal LJ, Cohen MA,
et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001;
50:2540 – 7.
[94] Yox DP, Brenner L, Ritter RC. CCK-receptor antagonists attenuate
suppression of sham feeding by intestinal nutrients. Am J Physiol
1992;262:R554 – 61.