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Am J Physiol Regul Integr Comp Physiol 291: R900 –R902, 2006;
doi:10.1152/ajpregu.00408.2006.
Editorial Focus
Hunger and satiety: one brain for two?
Thomas A. Lutz
Institute of Veterinary Physiology and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Address for reprint requests and other correspondence: Institute of Veterinary Physiology and Center of Integrative Human Physiology, Univ. of Zurich,
Winterthurerstrasse 260, 8057 Zurich, Switzerland (e-mail to tomlutz@
vetphys.unizh.ch).
R900
Nevertheless, it seems very likely that combination therapies
for obesity may have the same advantages of increased clinical
potency and decreased side effects that have been demonstrated in many other areas of pharmacological therapeutics.
Therefore, the study of interactions is an important area regarding their therapeutic potential. Basic research in this direction is relatively well advanced only in the case of CCK,
which has been reported to functionally interact with several
other peripheral signals that control eating, e.g., amylin, estradiol, gastric load, glucagon, leptin, and insulin (e.g., see Refs.
5, 6, 19, 22, and 34). With the exception of glucagon, all these
interactions are synergistic, i.e., eating was further decreased
when CCK and the other signal were applied simultaneously
compared with CCK alone. Very much less is known about
mechanistic vs. functional interactions. The synergistic interaction between CCK and amylin may reflect a necessary part of
CCK signaling because 1) amylin antagonists attenuated
CCK’s anorectic action in rats (17) and 2) the anorectic effect
of CCK was almost completely abolished in the complete
absence of endogenous amylin in knockout mice and was
rescued by small doses of amylin (19). These mechanistic
interactions are perhaps more relevant to physiology than to
pharmacology.
Insulin and leptin appear to act by increasing the sensitivity
of the brain to CCK as meal-generated signals contributing to
meal-ending satiation (21, 30, 33). Therefore, the integration of
these messages within the brain including the signals reflecting
body adiposity contributes to the sensation of satiation at meal
termination. Theoretically, when an individual is underweight,
the reduced adiposity signal allows larger meals to be consumed until weight is restored and vice versa.
Over the last two years, the group by Hubert Mönnikes and
colleagues published two interesting papers on the pharmacological interaction of the functional antagonist to leptin and
insulin, i.e., ghrelin, with the satiating peptides CCK (9),
bombesin (BB) and amylin (8). Kobelt et al. (9) found that
subthreshold doses of CCK abolished the orexigenic effect of
ghrelin when coadministered intraperitoneally. These experiments were complemented by immunohistochemical studies of
expression of c-Fos protein. Ghrelin induced a strong increase
in c-Fos expression in the hypothalamic arcuate (ARC) and
paraventricular nuclei (PVN), but not in the nucleus of the
solitary tract (NTS). CCK, on the other hand, induced c-Fos in
the NTS and the PVN, but not in the ARC. CCK, however,
completely reversed the ghrelin-induced c-Fos formation in
the ARC.
In the latest paper by Mönnikes and colleagues (Ref. 8), the
authors extend their previous study on CCK and ghrelin to
investigate now the possible interaction between BB and ghrelin, and amylin and ghrelin, respectively. Hence, this paper
deals with an almost forgotten peptide because BB and its
mammalian counterparts, gastrin-releasing peptide and neuromedin B, have not seen much interest over the last few years.
One reason for this relative lack of interest may arise from
some uncertainty about the true site of action (peripheral or
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controls of eating and developing effective pharmacological tools to reduce eating has
never been more important. The modern world faces an unprecedented obesity epidemic, and the current treatment strategies are rather unsuccessful. One possible solution may be a
combination or cocktail therapy. Obesity control research has
been more focused on “long-term” adiposity signals rather than
the control of individual meals, which has been assumed to be
rather plastic (34). Moreover, meal size appears to be under a
confusingly large number of controls (27, 30, 33, 34). One
potential reason for this is that avoiding excessive meal size
may be very important physiologically because large meals are
major physiological stresses (32) that, at some point, may be
unadaptive. This suggests that the controls of meal size, including many controls of the gut-brain axis, may indeed be
very potent and are likely to open efficacious therapeutic
opportunities. A related reason not to underemphasize the
potential of meal controls in obesity therapy is the increasing
evidence that the weight regulatory system based on leptin,
insulin, and other adiposity signals, in fact, seems more designed to stimulate eating and conserve energy when adiposity
levels are too low rather than to inhibit eating and expend
energy when adiposity increases (26).
The consequences of the multifactorial and redundant controls of eating in animals and humans for potential pharmacotherapy are ambiguous. It may be that manipulations of individual signals will be ineffective because of functionally antagonistic, adaptive responses by other signals. However, the
wealth of signals also creates the potential for therapies based
on simultaneous manipulation of several signals. If many
control signals operate simultaneously to control a single
behavior, they must interact.
This addresses an important point: is food intake truly a
single behavior? Total food intake being composed of many
individual meals is regulated by different control signals that
govern meal initiation, the maintenance of eating through
intrameal control mechanisms, meal-ending satiation, and intermeal satiety (e.g., see Ref. 28). Each one of these has to be
considered a single behavior and their physiological controls
may act independently. Therefore, signals that in pharmacological trials have been shown to interact, i.e., that 1) they
produce a more potent effect on food intake than each signal
alone or that 2) one of the signals reduces the effect of that
induced by the other, may not necessarily interact under
physiological conditions, especially if they govern different
behaviors within the overall control of food intake. Therefore,
one has to differentiate between physiological mechanistic
interaction of controls and the effect of combination therapy in
pharmacological trials that may only rely on a single measured
outcome, i.e., food intake.
UNDERSTANDING THE PHYSIOLOGICAL
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whereas CCK satiation involves the hypothalamic serotoninergic system, the dopaminergic and histaminergic systems
have been implicated in amylin signaling (13, 16, 18, 29).
The studies like Kobelt et al.’s (8, 9) focus the attention on
the crucial importance of identifying the specific neural projections from the NTS to hypothalamic nuclei but also vice
versa (3). Combinations of extensive phenotyping of neurons
might allow bidirectional analysis for the connections between
brain stem and hypothalamus. Studies only relying on c-Fos
cannot do this. Even though the authors concentrated more on
hypothalamic, rather than brain stem, mechanisms, the study of
satiating peptides, such as CCK, BB, and amylin and their
interaction with other hormones should also focus on interactions within the brain stem because of its importance for meal
size control (7).
Studies based on c-Fos response face the inherent problem
that c-Fos cannot provide information about neuronal inhibition. This shortcoming can, e.g., be partly overcome by combining the c-Fos technique with appropriate experimental designs. The fasting-induced c-Fos response in specific hypothalamic nuclei is, for example, reversed by refeeding the animals,
but also specifically by certain meal-related peptides, such as
shown for amylin in the lateral hypothalamic area (24). Another obvious problem of c-Fos staining is that it is unable to
yield information regarding the function of signals associated
with neuronal activation in a certain brain area. At first sight,
it seems unlikely that the increase in PVN c-Fos induced by
ghrelin and BB occurs in the same neurons and hence relate to
the same function, because the effects of ghrelin and BB on
feeding are opposite. Mönnikes and colleagues speculate, however, that this finding may indicate that ghrelin activates its
own counterregulatory mechanism to limit the amount of food
intake, and that this mechanism may be enhanced by BB via
CRF neurons (8).
This also brings back the issue raised before about the
difference between physiological control mechanisms of multiple behaviors involved in food intake and pharmacological
interaction. In other words, while ghrelin has been hypothesized to be one of the factors leading to meal initiation (4),
CCK, BB, and amylin are all thought to contribute to the
control of meal size by acting as meal-ending, satiating peptides (33). Hence, specific neurons identified by a positive
c-Fos response may be involved in different behaviors, and the
specific functional correlate being associated with this activation may, for example, depend on the temporal pattern of
activation, the metabolic context, and neuronal activation in
other brain areas.
As mentioned, extensive phenotyping of the neurons involved in the peptides’ effects in different brain regions and
colocalization of c-Fos expression with hormone receptors will
help to delineate the exact pathways of hormone action and
interaction. Obviously, if c-Fos expression induced by a certain
peptide does not colocalize with the hormone receptor, it is
very unlikely that this particular site of c-Fos expression
represents the primary site of action. Therefore, c-Fos staining
has to be combined with other techniques. Such combinations,
i.e., lesioning studies (15, 24, 35), local hormone administration (20), and staining for the receptor protein (2) helped, for
example, to delineate the AP as the most likely site of amylin
action (and interaction with ghrelin in respect to the regulation
of gastric ghrelin release).
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central) and the receptors involved in BB’s anorectic response
(33). In any event, the reemerging interest in the stomach as a
site of important controls of eating, such as ghrelin may have
led to the renewed interest in BB. At the same time, it would
have been useful if the authors had verified their results with
mammalian members of the BB family of peptides.
The other player in the current paper by Mönnikes and
colleagues (8), amylin, is synthesized by the pancreatic ␤-cells
and cosecreted with insulin. One of the best investigated
functions of amylin is its role as a hormonal control of
meal-ending satiation (11, 14). The effects of peripheral amylin
on eating seem to be mediated by amylin receptors in the area
postrema (AP) (15, 20, 24) and vagal and nonvagal visceral
afferents, in contrast to mediating the anorectic effects of CCK
and BB (22, 31), do not seem to be involved (12, 23).
Similar to the previous findings with CCK (9), Kobelt et al.
(8) now report that subthreshold doses of BB blocked the
orexigenic effect of ghrelin. In contrast to the previous results,
however, BB only slightly reduced ghrelin-induced c-Fos in
the ARC. Furthermore, although BB alone had no effect on
c-Fos expression in the PVN, it markedly enhanced ghrelininduced PVN c-Fos. Phenotyping of the neurons that were
activated by ghrelin alone, or by the combination of ghrelin
and BB, revealed that a considerable proportion of these
neurons were positive for corticotropin-releasing factor (CRF)
because ⬃50% of neurons were colabeled for c-Fos and CRF.
However, CRF-positive neurons mainly seem to subserve other
purposes because only about 20% of CRF neurons expressed
c-Fos after ghrelin and BB.
No interaction between the feeding response to amylin and
ghrelin was found. Furthermore, amylin had no effect on the
extent of c-Fos in the ARC or PVN. Although amylin reduces
fasting-induced c-Fos expression in the lateral hypothalamic
area of rats (24), it has not been tested whether this response is
affected by ghrelin. Furthermore, recent studies have shown
that amylin, via an action in the AP, affects ghrelin release
(35), but this was not the focus of the study by Kobelt et al. (8).
All in all, the two papers by Mönnikes and colleagues (8, 9)
extend our knowledge in respect to the pharmacological interaction of peptides that regulate feeding behavior. Although in
the case of CCK and amylin, the papers add up to the existing
literature, this is one of the very few studies investigating the
relationship between members of the BB family of peptides
and other peptidergic or nonpeptidergic controls of food intake
(e.g., Ref. 1). It seems likely that depending on the peptides,
different specific neuronal networks are involved in the interactions, and this is nicely exemplified by the c-Fos studies
indicating that ghrelin and BB interact in the PVN and that
ghrelin and CCK interact in the ARC. The negative data on a
possible interaction between ghrelin and amylin suggest that
interactions between ghrelin and CCK or ghrelin and BB,
respectively, are specific and not just the sum of individual
effects.
Amylin, BB, and CCK all elicit a positive c-Fos response in
the NTS, the lateral parabrachial nucleus, and the central
nucleus of the amygdala (10, 24, 25). What remains unknown
is whether the peptides activate different cell groups within the
NTS or different projections from NTS to the hypothalamus.
To find this out would, for example, require phenotyping of the
NTS neurons defining the different neurotransmitters that may
mediate the effects of the different peptides. For example,
Editorial Focus
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Open questions may be addressed in future experiments
using new imaging techniques (e.g., molecular in vivo imaging). These new imaging studies on the mechanism of action
and interaction of peptide hormones would largely benefit from
the possibility to assess temporal aspects of hormone action
because classical c-Fos studies have mostly been performed at
a single time point and therefore cannot yield such information.
Furthermore, these techniques may allow delineating the bidirectional pathways between brain stem and hypothalamus.
Such studies performed in natural feeding situations would
seem to be a logical sequel of the work by Kobelt et al. (8, 9)
to study the different roles that these hormones might subserve
in the control of meal pattern. Hence, studies both at the
behavioral and imaging level are warranted to understand fully
whether and how different peptide hormones interact and
which physiological behavior they govern.
To summarize, the two studies published by Kobelt et al.
provide important information regarding the interaction of
ghrelin with CCK, BB, and amylin. Like most of the interesting experiments, however, the data raise more new questions
than they can answer. Therefore, they open up new fields of
investigation that have to be pursued to better understand the
complex central nervous system network involved in the control of food intake and ultimately, body weight. This may
eventually lead both to improved physiological understanding
and improved pharmacotherapy for the treatment of obesity.