S U P P L E M E N T
R e v i e w
Central Control of Body Weight and Appetite
Stephen C. Woods and David A. D’Alessio
Departments of Psychiatry (S.C.W.) and Medicine (D.A.D.), University of Cincinnati, Cincinnati, Ohio 45237
Context: Energy balance is critical for survival and health, and control of food intake is an integral
part of this process. This report reviews hormonal signals that influence food intake and their
clinical applications.
Evidence Acquisition: A relatively novel insight is that satiation signals that control meal size and
adiposity signals that signify the amount of body fat are distinct and interact in the hypothalamus
and elsewhere to control energy homeostasis. This review focuses upon recent literature addressing the integration of satiation and adiposity signals and therapeutic implications for treatment
of obesity.
Evidence Synthesis: During meals, signals such as cholecystokinin arise primarily from the GI tract
to cause satiation and meal termination; signals secreted in proportion to body fat such as insulin
and leptin interact with satiation signals and provide effective regulation by dictating meal size to
amounts that are appropriate for body fatness, or stored energy. Although satiation and adiposity
signals are myriad and redundant and reduce food intake, there are few known orexigenic signals;
thus, initiation of meals is not subject to the degree of homeostatic regulation that cessation of eating
is. There are now drugs available that act through receptors for satiation factors and which cause
weight loss, demonstrating that this system is amenable to manipulation for therapeutic goals.
Conclusions: Although progress on effective medical therapies for obesity has been relatively slow
in coming, advances in understanding the central regulation of food intake may ultimately be
turned into useful treatment options. (J Clin Endocrinol Metab 93: S37–S50, 2008)
T
he past decade has seen an increasing recognition that a complex interplay exists between the central nervous system
(CNS) and the activity of numerous organs involved in energy
homeostasis. This requires the transmission of key information
to the brain, and control of food intake is one component of
energy balance where endocrine signaling from the periphery to
the CNS has a particularly important role. Considered broadly,
energy homeostasis consists of the interrelated processes integrated by the brain to maintain energy stores at appropriate
levels for given environmental conditions. Energy homeostasis
thus includes the regulation of nutrient levels in key storage organs (e.g. fat in adipose tissue and glycogen in the liver and
elsewhere) as well as in the blood (e.g. blood glucose). To accomplish this, the brain receives continuous information about
energy stores and fluxes in critical organs, about food that is
being eaten and absorbed, and about basal and situational energy needs by tissues. The brain in turn controls tissues that have
important roles in energy homeostasis, like the liver and musculoskeletal system, as well as the secretion of key metabolically
active hormones, primarily through the autonomic nervous system. The brain is thus able to respond to ongoing as well as
unanticipated demands via well-coordinated responses to prevent shortfalls in energy stores while maintaining biochemical
homeostasis. This review focuses on hormonal and related signals that inform the brain of energy levels, thereby influencing
energy intake and ultimately body weight.
As a general rule, signals arising in the periphery that influence food intake and energy expenditure can be partitioned into
two broad categories (Fig. 1) (1–3). One comprises the signals
generated during meals that cause satiation (i.e. feelings of full-
0021-972X/08/$15.00/0
Abbreviations: AgRP, Agouti-related peptide; apo A-IV, Apolipoprotein A-IV; ARC, arcuate
nucleus; CCK, cholecystokinin; DPP-IV, dipeptidyl peptidase IV; GI, gastrointestinal; GLP-1,
glucagon-like peptide-1; GLP-1r, GLP-1 receptor; GRP, gastrin-releasing peptide; LHA,
lateral hypothalamic area; MC3R, melanocortin 3 receptor; MC4R, melanocortin 4 receptor; ␣MSH, ␣-melanocyte-stimulating hormone; NMB, neuromedin B; NPY, neuropeptide-Y; POMC, proopiomelanocortin; PVN, paraventricular nuclei; PYY, peptide
tyrosine-tyrosine.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2008-1630 Received July 28, 2008. Accepted September 8, 2008.
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
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J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
FIG. 1. Model summarizing different levels of control over energy homeostasis. During meals, signals such as CCK, GLP-1, and distension of the stomach that arise
from the gut (stomach and intestine) trigger nerve impulses in sensory nerves traveling to the hindbrain. These satiation signals synapse with neurons in the nucleus of
the solitary tract (NTS) where they influence meal size. Ghrelin from the stomach both acts on the vagus nerve and stimulates neurons in the ARC directly. Signals
related to body fat content such as leptin and insulin, collectively called adiposity signals, circulate in the blood to the brain. They pass through the blood-brain barrier
in the region of the ARC and interact with neurons that synthesize POMC or NPY and AgRP. ARC neurons in turn project to other hypothalamic areas including the
PVN and the LHA. The net output of the PVN is catabolic and enhances the potency of satiation signals in the hindbrain. The net output of the LHA, on the other hand,
is anabolic, suppressing the activity of the satiation signals. In this way body fat content tends to remain relatively constant over long intervals by means of changes of
meal size.
ness that contribute to the decision to stop eating) and/or satiety
(i.e. prolongation of the interval until hunger or a drive to eat
reappears). The prototypical satiation signal is the duodenal peptide cholecystokinin (CCK), which is secreted in response to dietary lipid or protein and which activates receptors on local sensory nerves in the duodenum, sending a message to the brain via
the vagus nerve that contributes to satiation. The second category includes hormones such as insulin and leptin that are secreted in proportion to the amount of fat in the body. These
“adiposity” hormones enter the brain by transport through the
blood-brain barrier and interact with specific neuronal receptors
primarily in the hypothalamus to affect energy balance. Satiation
and adiposity signals interact with other factors in the hypothalamus and elsewhere in the brain to control appetite and body
weight, and they are the topic of this review.
Body weight (adiposity) is a homeostatically regulated variable, and its long-term maintenance can only occur via a close
linkage of energy intake to energy expenditure. This means that
over long intervals, the amount of food consumed must provide
energy equivalent to the amount of energy expended. Humans
and most mammals acquire energy in discrete episodes or meals.
For many modern-day humans, the impetus to begin a meal is
rarely if ever based on a biological deficit or need such as insufficient glucose. Rather, “appetite” and “hunger” occur, and
meals are initiated based on habit, time of day, specific social
situations, convenience, or stress, factors that are not linked to
energy needs and so are nonhomeostatic (4 – 6). Arguably, this
has been the case throughout human evolution as well, with the
initiation of feeding governed by nonhomeostatic factors such as
food availability or having a safe haven to eat. Thus, the homeostatic influence over food intake is often left to the control over
how many calories are consumed once a meal begins; i.e. on meal
size. Consistent with this, many of the secretions of the gastrointestinal (GI) tract during a meal, such as CCK, are proportional
to the number of calories consumed, and some of these secretions
function as satiation signals to the CNS to help limit meal size (see
reviews in Refs. 7–9).
In contrast to satiation signals that are phasically secreted
during meals, adiposity signals are more tonically active, providing an ongoing message to the brain proportional to total
body fat. Insulin is tonically secreted in basal amounts, with
phasic increments occurring during meals, and both components
of total insulin secretion (i.e. basal and meal-stimulated) are directly proportional to body fat (10). Leptin is secreted in direct
proportion to body adiposity, following a diurnal pattern with
less direct connection to meals than insulin (11). As an individual
changes body weight through caloric restriction or overeating,
the amounts of insulin and leptin secreted into the blood change
in parallel, and this in turn is reflected as an altered signal of body
fatness, tantamount to body energy stores, reaching the brain
(1–3). These adiposity signals interact with anabolic and catabolic neural circuits, causing a change in sensitivity of the brain
to satiation signals. For example, during food deprivation or
dieting, reduced brain insulin/leptin signaling renders neural cir-
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
cuits controlling meal size less sensitive to satiation signals such
as CCK. As a consequence, the homeostatic setting is geared for
the intake of larger meals because more food must be consumed
before a sufficient satiation signal is generated to stop eating.
This situation of extra-large meals persists until body weight
(and hence the insulin/leptin signal) returns to normal. Conversely, after excessive weight gain, the increased insulin/leptin
brain signal results in increased sensitivity to satiation signals,
and smaller meals are consumed until the excess weight is lost. A
major dilemma facing clinicians and others involved in public
health is the slippage in the latter limb of this homeostatic system
that permits excessive energy storage, obesity, and the associated
diseases of nutritional excess; e.g. diabetes, cardiovascular disease, and some cancers.
Satiation Signals
By definition, satiation factors, when administered to humans or
animals at the start of a meal, result in a smaller-than-normal
meal being consumed. Exogenously administered satiation factors, or endogenous secretion of these compounds, activates specific receptors that cause premature cessation of eating. There are
several excellent reviews of satiation signals such that only the
salient points need to be reviewed here (7–9, 12–14). It is generally accepted that for an endogenous compound to be considered a satiation signal, it is secreted in response to food ingestion,
acts within the time frame of a single meal, reduces meal size
without creating malaise or incapacitation, and is effective at
physiological doses, and removing or antagonizing its endogenous activity increases meal size (7, 15).
The best-established satiation signals are secreted from specialized enteroendocrine cells in the wall of the GI tract in response to the digestion and absorption of meals. In the classic
model of satiation, local sensory nerves express receptors for
these gut peptides as they are secreted such that the brain is
immediately informed about the nutritional content of the meal
by monitoring the level of hormones secreted to cope with it. As
a complex meal is consumed, the mix of macronutrients (carbohydrates, fats, and proteins) stimulates a proportional blend of
satiation peptides, and an overall message indicating meal content is integrated in the hindbrain where it activates appropriate
responses, including ultimately cessation of the meal. In humans,
this is associated with a sensation of fullness. Although not all
intestinal hormones double as satiation signals, they all presumably contribute to the assimilation of nutrients; i.e. by stimulating the secretion of appropriate enzymes, water, and other compounds into the lumen of the gut and regulating GI motility.
Table 1 provides a list of GI and other meal-related hormones/
peptides that are generally considered to be satiation signals.
Cholecystokinin
CCK was the compound first identified to fit the criteria for
a satiation factor, so that much is known about its actions. Consequently, CCK has become the model for the larger class of
satiation factors. When food containing fat or protein is consumed and enters the duodenum, CCK is secreted from I cells.
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TABLE 1. GI hormones that affect satiation
Peptide
Effect on food intake
CCK
GLP-1
PYY
Apo A-IV
Enterostatin
Bombesin/GRP/NMB
Oxyntomodulin
Amylin
Ghrelin
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Increase
CCK enters the blood and has hormonal influences on gut motility, contraction of the gallbladder, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion (16 –19). However, CCK also diffuses locally to provide a paracrine stimulus to
CCK-1 receptors on nearby branches of vagal sensory nerves
(20 –23). Through this mechanism a message, generally that ingested fat/protein is being processed and will soon be absorbed,
is conveyed to the hindbrain and relayed to the hypothalamus
where it is integrated into the composite information on energy
homeostasis (20, 24 –28) (Fig. 2).
The decrease of meal size elicited by exogenous CCK is dosedependent, with higher doses causing greater reductions of meal
size. However, CCK does not prevent meals from occurring;
rather, it decreases the size of the meal once it has begun, reducing
hunger and increasing fullness without concomitant sensations
of illness or malaise. When a CCK-1 receptor antagonist is administered before the presentation of food to animals or humans,
larger-than-normal meals are consumed (29 –31), providing
compelling evidence that endogenous CCK normally acts to sup-
FIG. 2. Satiation signals arising in the GI system converge on the dorsal
hindbrain (D) where they are integrated with taste and other inputs. The dorsal
hindbrain makes direct connections with the ventral hindbrain (V) where neural
circuits direct the autonomic nervous system to influence blood glucose and
where the motor control over eating behavior is located. The dorsal hindbrain
also conveys information on satiation and other factors anteriorly to the
hypothalamus and other brain areas. These areas in turn integrate satiation and
adiposity signals as well as available nutrients with experience, the social situation
and stressors, and with time of day and other factors. The integrated information
is then conveyed posteriorly back to the ventral hindbrain as well as to the
pituitary to influence all aspects of energy homeostasis. Animals lacking neural
connections between the hindbrain and the hypothalamus reduce the intake of
individual bouts of eating when the stomach is distended or they are
administered CCK. However, those animals cannot regulate their body weight
and are not sensitive to past experience, time of day, or social factors (243).
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press intake during meals. However, the effect of exogenous
CCK is short-lived; the meal-reducing signal does not carry over
to a second meal. Moreover, the effect of repeated or chronic
administration of CCK (32, 33) has no effect on body weight
because the short-term regulation of meal size is overridden by
overall energy balance. That is, in the context of lower adiposity,
leptin and insulin signals to the brain are reduced and satiation
factors like CCK have a reduced effect to restrict meal size.
There is strong experimental evidence supporting a role for
CCK as a satiation factor in humans. CCK levels increase after
meals, and infusion of an exogenous CCK-1 receptor agonist,
CCK-33, to postprandial levels suppresses food intake (34, 35).
Furthermore, infusion of a CCK-1 receptor antagonist to healthy
humans causes an increase in caloric intake, strongly implicating
endogenous CCK as a brake on meal size (29, 36). The effects of
CCK-1 agonism and antagonism are similar in lean and obese
humans and are associated with appropriate changes in hunger
and fullness. Interestingly, blockade of CCK-1 receptors affects
the postprandial responses of other GI hormones, attenuating
the usual rise in peptide YY (PYY) and abolishing the suppression of ghrelin (37). This latter finding suggests that beyond
directly inhibiting food intake, CCK acts as a proximal mediator
of the broader satiation process. Two minor single nucleotide
polymorphisms in the CCK-1 receptor gene promoter have been
associated with increased body fatness, but the mechanism of
this association has not been explained (38).
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is derived from proglucagon in intestinal L cells that are most prevalent in the ileum and
colon (39). GLP-1 secretion is elicited by nutrients, but the mechanism whereby the distal L cells are stimulated early within meals
may require neurohumoral signals initiated in the proximal regions of the small intestine (40). GLP-1 has a broad range of
actions on glucose metabolism (41), most prominently stimulation of insulin secretion, but also inhibition of glucagon release.
Because GLP-1 inhibits GI motility and secretions, it has been
implicated as a major component of the “ileal brake,” an inhibitory feedback mechanism that regulates transit of nutrients
through the course of the GI tract (42, 43). It has generally been
assumed that GLP-1 mediates these various actions through an
endocrine mechanism, by binding directly to key target tissues
like pancreatic islet cells. However, this mechanism has recently
been called into question, in large part because GLP-1 is rapidly
metabolized in the circulation by the protease dipeptidyl peptidase IV (DPP-IV) (44). Indeed, the half-life of GLP-1 in human
plasma is only 1–2 min, and the product of DPP-IV action, a
truncated GLP-1, is inactive with regard to glucose metabolism
(45). Because the GLP-1 receptor (GLP-1r) is expressed by peripheral and CNS neurons as well as by cells in the pancreatic
islets and the GI tract, recent attention has focused on neural
mechanisms of GLP-1 action (46 – 48).
GLP-1 administration reduces food intake in animals and
humans (49 –54), and these anorectic actions are thought to be
mediated through both peripheral and central mechanisms. A
population of neurons that synthesize GLP-1 is located in the
brain stem and projects to hypothalamic and brain stem areas
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important in the control of energy homeostasis (55, 56). Centrally administered GLP-1 reduces food intake through at least
two mechanisms. GLP-1r in the hypothalamus appear to reduce
intake by acting on caloric homeostatic circuits (57– 60),
whereas GLP-1r in the amygdala reduce food intake by eliciting
symptoms of stress or malaise (61, 62).
Systemically administered GLP-1 elicits satiation in healthy
(53), obese (63), and diabetic (64, 65) humans. Because the halflife of active GLP-1 is less than 2 min, any direct effects are likely
transient, and the reduction of food intake may result from inhibitory effects of GLP-1 on GI transit and reduced gastric emptying (66). However, peripherally administered GLP-1 does
cross the blood-brain barrier (67), perhaps enabling circulating
GLP-1 to interact with the brain GLP-1r. Because it both reduces
food intake and stimulates insulin secretion, the GLP-1 system
has been adapted to the treatment of type 2 diabetes (68, 69).
DPP-IV-resistant, long-acting GLP-1r agonists are effective at
reducing blood glucose in persons with type 2 diabetes and also
cause weight loss (70). In addition, inhibitors of DPP-IV, which
elevate endogenous GLP-1 levels, are also effective at improving
glycemic control in diabetic patients (71, 72).
The effect of chronic GLP-1r agonists to cause weight loss is
not consistent with the general principle that satiation peptides
are subservient to long-term regulators of energy balance, such
as leptin (3). One potential explanation is that because GLP-1
can activate nonhomeostatic pathways that suppress food intake
and otherwise reduce body weight, the effects of chronic administration of GLP-1r agonists work around the homeostatic systems controlling body weight. Indeed, nausea, a hallmark feature
of nonhomeostatic anorexia, is very common with GLP-1r agonist treatment (73), although this response wanes with continued treatment and is not present in all persons who lose weight.
Another possible explanation for why patients treated with indictable GLP-1r agonists lose weight is that repeated pharmacological doses of a satiation signal can overcome homeostatic
restraints. Consistent with this hypothesis is the failure of
DPP-IV inhibitor treatment, which has a smaller effect to raise
circulating concentrations of GLP-1r agonist activity than do
injectable GLP-1 mimetics to cause weight loss. Although it is not
yet clear how GLP-1r agonists cause weight loss, the fact that
they do challenges the current model of the interaction of satiation factors with overall energy homeostasis.
Glicentin, GLP-2, oxyntomodulin, and glucagon
Other peptides derived from the processing of proglucagon
include glicentin, GLP-2, and oxyntomodulin, as well as glucagon itself (39). Glicentin inhibits gastric acid secretion (74), but
at least in rats, does not affect food intake (75). In contrast,
oxyntomodulin, a C-terminally extended congener of glucagon,
does reduce food intake in animals when given centrally or peripherally (75, 76). Although a unique receptor for oxyntomodulin has yet to be identified, oxyntomodulin may exert its anorectic effect through the GLP-1r because subthreshold doses of
the GLP-1r antagonist, exendin (9 –39), block both GLP-1 and
oxyntomodulin-induced reductions in food intake (75). Oxyntomodulin is thought to cross the blood-brain barrier and stimulate neurons in the arcuate nucleus (ARC) that express GLP-1r
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and control energy homeostasis (77, 78). Long-term treatment
with oxyntomodulin causes a persistent decrease in food intake
and attenuated weight gain in rats (79). Interestingly, weight loss
in animals given oxyntomodulin chronically is greater than what
would be anticipated from reduced caloric intake (78), suggesting additional effects on energy expenditure.
Short-term treatment with iv oxyntomodulin decreases hunger, reduces consumption of an ad libitum meal, and has an
anorectic action that persists for 12 h after cessation of treatment
in lean humans (80). Moreover, in obese subjects randomized to
injections of oxyntomodulin or placebo before each meal for 4
wk, there was a significant loss of weight associated with active
treatment. Oxyntomodulin caused an approximately 0.5 kg/wk
reduction in body weight and was generally well tolerated. These
findings suggest that at least two proglucagon products may have
a role in the regulation of food intake. Distinguishing between
the effects of GLP-1 and oxyntomodulin, in particular the relative in vivo actions on the GLP-1r, is an important next step in
applying these compounds to clinical medicine.
GLP-2 acts through a specific GLP-2 receptor to stimulate
intestinal mucosal growth and has become the focus of research
on short-bowel syndrome (81, 82). GLP-2 and GLP-1 have
nearly 50% sequence homology and are secreted in parallel from
perfused ileal preparations (83). Intracranial administration of
GLP-2 reduces food intake in rats, and the effect can be blocked
with a specific GLP-1r antagonist (84). More recent studies in
humans found no effect of iv GLP-2 on food intake (85).
Glucagon is the most widely studied hormone cleaved from
preproglucagon (39). It is secreted from both pancreatic A cells
and probably also in small amounts from the distal intestine. The
best known action of glucagon is to increase hepatic glucose
production by stimulating glycogenolysis and gluconeogenesis.
Glucagon also reduces meal size when administered systemically
(86, 87), but not centrally (88), the signal being detected in the
liver and relayed to the brain (89). A role for glucagon in the
normal control of meal size was demonstrated by the observation
that blocking endogenous glucagon action in rats increases food
intake (90, 91). There is little convincing evidence that glucagon
plays a role in food intake in healthy humans.
Peptide tyrosine-tyrosine (PYY)
PYY is a member of a family of homologous peptides that also
includes pancreatic polypeptide and neuropeptide-Y (NPY).
Like proglucagon-derived peptides, PYY is synthesized and secreted by L cells in the distal ileum and colon (92). PYY is secreted
as PYY (1–36) and is metabolized to PYY (3–36) by DPP-IV (93,
94). Receptors that mediate the effects of PYY, including reduction of food intake, belong to the NPY receptor family and include Y1, Y2, Y4, and Y5 (95). However, PYY (3–36) is a highly
selective agonist activity for the Y2 receptor, and it also reduces
food intake in humans and animals (96, 97). Like GLP-1, PYY
has been implicated in GI motility and is considered a major
component of the ileal brake (98, 99). Secretion of PYY is stimulated by food intake (100) and also by the presence of nutrients
within the ileum itself (101); lipid seems to be a particularly
effective stimulus. Similar to the case with GLP-1, it is not clear
whether PYY release requires direct nutrient contact with L cells,
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or if neurohumoral signals originating from the more proximal
GI tract mediate the response. There is evidence that PYY influences food intake through its interaction with Y2 receptors in the
ARC because it freely crosses the blood-brain barrier (102) and
because systemic PYY (3–36) is ineffective in reducing food intake in the Y2-deficient mouse (103).
Studies in humans have demonstrated that PYY signaling reduces food intake and that abnormalities in this system are
present in obese subjects. PYY secretion is proportional to the
caloric content of meals, with larger meals eliciting a significantly
larger response (104, 105). Fasting and postprandial levels of
PYY are lower in obese adults compared with lean controls (105,
106). The attenuated rise in PYY after eating has also been observed in obese adolescents (107). Infusion of PYY (3–36) into
lean and obese humans reduced food consumption measured
during test meals (104 –106), although there remains some question as to whether this effect of PYY (3–36) is pharmacological
or occurs at circulating levels seen after eating. Obese subjects did
not differ in their sensitivity to PYY, and there was no difference
in the relative PYY (1–36) and PYY (3–36) levels after exogenous
administration. Taken together, these findings suggest that abnormal PYY production, rather than anorectic action of metabolism, could contribute to obesity.
Interestingly, there is evidence that genetic variations in the
PYY and Y2 sequences are associated with body weight. A common gene polymorphism in the Y2 receptor has been associated
with a reduced likelihood of obesity in a cohort study of men with
a broad range of BMI (108). Additionally, in a survey of lean and
very obese men, a polymorphism in the PYY allele was found to
segregate with increased body weight; this genetic variant of PYY
was also found to have reduced binding to its receptor and an
attenuated anorectic effect in mice (109). In total, the data collected in human studies support a role for PYY in the regulation
of food intake and build the strongest case for any of the satiation
factors in the pathogenesis of obesity.
Apolipoprotein A-IV
Apolipoprotein A-IV (apo A-IV) is synthesized by intestinal
mucosal cells during the packaging of digested lipids into chylomicrons that subsequently enter the blood via the lymphatic
system (110). Apo A-IV is also synthesized in the ARC (111).
Systemic or central administration of apo A-IV reduces food
intake and body weight of rats (112), and administration of apo
A-IV antibodies increases food intake (113). Apo A-IV appears
to work by interacting with the CCK signal (114). Because both
intestinal and hypothalamic apo A-IV are regulated by absorption of lipid but not carbohydrate (115), this peptide may be an
important link between short- and long-term regulators of body
fat (see review by Tso and Liu in Ref. 116).
Enterostatin
A second digestion-related peptide, enterostatin, is also
closely tied to intestinal processing of lipid. The exocrine pancreas secretes lipase and colipase to aid in the digestion of fat, and
enterostatin, a pentapeptide, is cleaved from colipase in the intestinal lumen and enters the circulation. Administration of exogenous enterostatin either systemically (117, 118) or directly
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into the brain (119) reduces food intake, and, when rats are given
a choice of foods, the reduction is specific for fats; that is, enterostatin does not decrease the intake of carbohydrate or protein (120). Therefore, two peptides that are secreted from the gut
during the digestion and absorption of lipids, apo A-IV and enterostatin, act as signals that decrease food intake, and at least
one of them selectively reduces the intake of fat. Macronutrient
specificity has not been assessed with apo A-IV. There are no data
from human studies to confirm the findings with apo A-IV and
enterostatin on food intake.
Bombesin-family peptides
Members of the bombesin family of peptides including bombesin itself (an amphibian peptide) and its mammalian analogs,
gastrin-releasing peptide (GRP) and neuromedin B (NMB), reduce food intake when administered systemically in humans and
animals or into the CNS of animals (121–123). Consistent with
the possibility that these peptides act endogenously to reduce
food intake, mice deficient for the GRP receptor eat significantly
larger meals and develop late-onset obesity (124). Whereas most
satiation factors act by reducing the size of an ongoing meal (4),
bombesin peptides are an interesting exception in that when they
are administered between meals, they increase the amount of
time until the subsequent meal begins; i.e. they increase satiety as
well as satiation (125, 126).
Both bombesin and GRP reduce food intake when infused
into human subjects (127, 128). Antagonism of endogenous
bombesin receptors has demonstrable effects on gastric, intestinal, and gallbladder function but has not been studied with regard to food intake (129, 130). Therefore the case for GRP as a
physiological mediator of satiation in humans is not as strong as
for CCK.
Amylin
Amylin (also called islet amyloid polypeptide) is a peptide
hormone secreted by pancreatic B cells in tandem with insulin
secretion, which inhibits gastric emptying and gastric acid secretion, lowers glucagon concentrations, and reduces food intake (131). Amylin causes a dose-dependent reduction of meal
size when administered systemically or directly into the brain
(132–136), and antagonism of amylin action in the CNS causes
increased food intake and body weight (137). Consistent with
this, targeted deletion of the amylin gene causes increased body
weight in mice.
Amylin signals through the calcitonin receptor when it has
been modified by receptor activity modifying proteins (138,
139), and in contrast to many satiation peptides that reduce food
intake by stimulating the visceral afferent nerves, amylin seems
to act as a hormone, directly stimulating neurons in the area
postrema in the hindbrain (133, 140). In fact, the anorectic action of amylin shares features with both satiation signals (phasic,
meal-induced secretion) and adiposity signals (chronic interruption of action in rodents causes increased body fatness). Amylin
seems to interact with both types of regulation in that the ability
of amylin to reduce meal size is augmented when brain insulin
action is elevated (141) and the effects of CCK and bombesin are
muted in the absence of amylin signaling (142).
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Amylin has been developed as a therapeutic, with the synthetic analog pramlintide now available for the treatment of type
1 and type 2 diabetes and clinical trials under way to determine
the efficacy in treating obesity. In diabetic patients treated with
pramlintide for 1 yr, weight loss averaged approximately 2 kg
relative to placebo-treated controls (143, 144). Similar to treatment with the GLP-1r agonist exendin-4, pramlintide presents
supraphysiological levels of amylin-like activity to patients, and
the primary side effect is nausea. Nonetheless, the clinical experience with pramlintide supports the idea that chronic activity of
a satiating compound can cause weight loss.
Ghrelin
Ghrelin, a product of specific endocrine cells in the stomach
and duodenum, actually stimulates food intake and is the most
potent known circulating orexigen (145). Ghrelin is secreted
from the fundic region of the stomach and has been identified as
the endogenous ligand for the GH secretagogue receptor. Fasting
increases plasma ghrelin (146), and exogenous ghrelin increases
food intake when administered peripherally or centrally (147–
149). Ghrelin has also been linked to the anticipatory aspects of
meal ingestion because levels peak shortly before scheduled
meals in humans and rats (150) and fall shortly after meals end.
Moreover, elevated ghrelin has been linked to the hyperphagia
and obesity of individuals with the Prader-Willi syndrome (151).
Ghrelin is also unique among the GI signals in that its message
appears to be conveyed directly to receptors in the hypothalamus
(152–155), although, as is the case for CCK, GLP-1, and other
GI signals, there are ghrelin receptors on vagal sensory nerves
(156) but they do not appear to signal satiation (157).
Satiation signals: summary of general principles
Satiation appears to be a complex phenomenon, mediated by
a number of GI peptides. Although it is clear that the different
satiation factors respond to specific nutrient stimuli (e.g. CCK to
protein and fat, GLP-1 to carbohydrate and fat, PYY primarily
to fat, and so on), it has not been proven that mixed meals of
differing macronutrient content elicit the release of distinct cocktails of GI hormones. However, given the wide range of specific
factors that seem to mediate satiation, it is logical to presume that
this process is subject to highly refined regulation. Especially
important is the modulation of the action of satiation by factors
such as leptin and insulin that are responsive to body adiposity.
This interaction is the critical site of endocrine regulation of
eating and energy homeostasis.
A key feature of the system regulating food intake is that most
if not all of the peptides that are made in the GI tract and influence
satiation are also synthesized in the brain. This includes CCK,
GLP-1, GLP-2, oxyntomodulin, apo A-IV, GRP, NMB, PYY,
and ghrelin. Exceptions are the pancreatic hormones that influence energy homeostasis (i.e. insulin, glucagon, and amylin) and
the adipose tissue/stomach hormone leptin; and each of these
latter hormones has long-term effects on body fat as well. The
fact that so many peripheral signals that influence food intake are
also synthesized locally in the brain raises the question of
whether and how the same signals secreted from different places
in the body interact. A simple generalization is that, if a peptide
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
reduces (or increases) food intake when administered systemically, it probably has the same action when administered centrally. With regard to changes of food intake, this is true of CCK,
GLP-1, apo A-IV, GRP, NMB, PYY, and ghrelin. Interestingly,
it is also generally true that peptide signals that are not synthesized in the brain nonetheless have the same effect on food intake
when administered directly into the brain. This is true of leptin,
insulin, and amylin, but not glucagon.
It is worth contemplating why there is such a large imbalance
among GI hormones that suppress and stimulate food intake; i.e.
whereas numerous peptides secreted from the stomach and intestines decrease food intake, only one known factor, ghrelin,
increases it. One possibility relates to the phenomenon of satiation itself and the benefits of meal termination. Meals end long
before any physical limit of the stomach is reached. This is easily
demonstrated when food is diluted with noncaloric bulk and
animals increase the volume of food consumed to attain their
normal caloric load (158, 159). It has therefore been argued that
a primary function of satiation signals is to prevent the consumption of too many calories at one time, lest the influx of nutrients
and substrates overwhelm the capacity of the animal to maintain
homeostasis (5, 160). That is, an important role of the GI tract
is to analyze and respond to the incoming macronutrients while
a meal is being eaten, helping to preempt excessive challenges to
biochemical homeostasis. A corollary to this role for satiation
signals is that adequate food intake does not require much specific stimulation, only the absence of inhibitory signals for food
intake combined with the presence of food. Until recently there
was some question as to whether manipulation of meal size by
factors activating the satiation system could have therapeutic
efficacy for weight reduction. One possibility was that because
the effects of satiation peptides are dependent on body adiposity,
their action would become muted as food intake decreased
due to homeostatic regulation of body energy stores. Evidence
for this was demonstrated for the satiating action of CCK in
genetically obese Zucker rats (161, 162), but not for rats rendered obese by lesions of the ventromedial hypothalamus (163).
Furthermore, rats genetically prone to becoming obese when fed
a high-fat diet (diet-induced obesity rats) are actually more sensitive to the satiating action of CCK both before and after becoming obese (164). Some strains of genetically obese mice are
comparably as sensitive as lean controls (165), and CCK works
well in obese humans when administered iv (166). Hence, there
is no general principle with regard to sensitivity in obesity, at
least with regard to CCK. There is evidence that the satiating
action of GLP-1 is leptin-dependent (167). All of these observations were made with animals having relatively free access to
their diets so that they could vary their meal patterns in the
service of maintaining body fat; i.e. when individuals are constrained to eating only small meals, they compensate by eating
more often, thereby maintaining daily caloric intake and body
weight. This has been observed when CCK is administered before every meal in experimental animals; animals receiving this
treatment eat smaller and more frequent meals while keeping
body weight constant (33, 168). In contrast, if animals are constrained to eating only three meals a day and receive a satiating
peptide at each mealtime, they cannot compensate and conse-
jcem.endojournals.org
S43
quently lose weight (169). The advent of long-acting formulations of GLP-1 and amylin, peptides that seem to have a role in
satiation (170, 171), has resulted in weight loss (172, 173). However, at present it is not clear that the chronic effects of GLP-1 and
amylin receptor agonists are entirely due to continued hypophagia as opposed to other, nonbehavioral actions of the compounds. Understanding how a chronic pharmacological stimulus
to the satiation system lowers body weight is important for refining the models for normal energy homeostasis.
Adiposity Signals
Insulin from the pancreatic B cells and leptin from white adipocytes (as well as the stomach and other tissues) are each secreted
in direct proportion to body fat. Both hormones are transported
through the blood-brain barrier (174, 175) and gain access to
neurons in the hypothalamus and elsewhere in the brain to influence energy homeostasis. Hence, neurons sensitive to insulin
and/or leptin receive a signal directly proportional to the amount
of fat in the body. Consistent with this, if exogenous insulin or
leptin is added locally into the brain, the individual responds as
if excess fat exists in the body; i.e. food intake is reduced and
body weight is lost. Analogously, if either the leptin or the insulin
signal is reduced locally in the brain, the individual responds as
if insufficient fat is present in the body, more food is eaten, and
the individual gains weight. There are many reviews of these
phenomena (1, 2, 87, 176 –178).
An important distinction is that whereas satiation signals primarily influence how many calories are eaten during individual
meals, adiposity signals are more directly related to how much fat
the body carries and maintains. Developing novel compounds
that interact directly with the normal detection of and response
to adiposity signals would therefore seem a more promising therapeutic approach for obesity. A key question therefore is whether
agonists for the leptin and/or insulin receptor would be viable
targets for the pharmaceutical industry. One obstacle is that to
be effective, any compound would have to gain access to key
receptors in the brain, yet any such compound would most likely
have to be administered systemically. Administering insulin systemically elicits hypoglycemia and other side effects, and hypoglycemia per se increases food intake (179 –181), thus working
against the therapeutic intent. Systemically administered insulin
does result in reduced food intake when plasma glucose is prevented from decreasing in animal models (182, 183), but this
would be difficult to achieve therapeutically. Alternatively, there
are reports that some formulations of nasally administered insulin elicit reduced food intake and body weight in humans without altering plasma glucose (184, 185).
Leptin does not have the same counterproductive systemic
effects as insulin, and in fact improves insulin sensitivity and
circulating lipoprotein concentrations in subjects with metabolic
abnormalities associated with anti-HIV treatment (186). Moreover, chronic leptin treatment of patients with generalized lipodystrophy causes significant improvements of insulin resistance,
hypertriglyceridemia, hepatic steatosis, and glucose metabolism
(187), responses found across the spectrum of lipodystrophies.
S44
Woods and D’Alessio
Central Control of Body Weight and Appetite
However, the results of clinical trials using leptin in healthy obese
subjects have been variable, with significant weight loss, but not
of a remarkable magnitude, and some bothersome side effects
related to peptide administration.
Insulin and leptin resistance characterize the obese state,
meaning that more of each hormone is required to achieve a
particular physiological effect than occurs in lean individuals.
Individuals with diabetes cannot achieve a maximum insulin
response because of defects in insulin secretion and insulin action. The insulin and leptin resistance that characterizes peripheral tissues in obesity is also manifested in the brain. For one
thing, the transport of both hormones from the blood to the brain
is compromised in obesity such that less signal reaches critical
neurons (188 –190), and the ability of those neurons to respond
is also compromised. When insulin is administered locally into
the brain near the hypothalamus, both genetically obese (191)
and dietary obese individuals (192) have a reduced or absent
reduction of food intake, and this is the case for leptin as well
(193). Hence, an inability on the part of the brain to respond to
signals indicating that there is excess fat in the body may be a
contributing and/or confounding factor in obesity. An insulin
mimetic that interacts with the insulin receptor and is efficacious
when given orally or directly into the brain has been reported to
reduce food intake and body weight in obese rodents (194, 195),
but it evidently has problematic side effects.
Central Integrating Circuits
Although receptors for insulin and leptin are found in several
discrete areas throughout the brain, many that are especially
important for controlling energy homeostasis are localized in the
ARC of the hypothalamus (Fig. 1). The ARC is ideally suited as
a receptor site for body adiposity as well as for integration of
diverse hormonal and neural signals because there is evidence
that blood-borne molecules have relatively greater access to receptors there than to other brain areas, and this is thought to be
due in part to a relatively leaky blood-brain barrier in the ARC
(196, 197). Two categories of ARC neurons are particularly important. One synthesizes the prepropeptide, proopiomelanocortin (POMC), and in the ARC POMC is cleaved to ␣-melanocytestimulating hormone (␣MSH) as a neurotransmitter. ␣MSH acts
at melanocortin 3 and melanocortin 4 receptors (MC3R and
MC4R) on neurons in other hypothalamic areas and elsewhere
in the brain to reduce food intake, and synthetic agonists for
MC3R/MC4R are available that cause hypophagia and
weight loss in experimental animals (see reviews in Refs. 1, 2,
196, and 198 –202). The catabolic action of both leptin and
insulin relies upon ␣MSH signaling because administration of
antagonists to MC3R/MC4R blocks each of their actions in
the brain (203, 204).
The second group of ARC neurons synthesizes and secretes
two neuropeptides important in energy homeostasis, and their
axons project to many of the same brain areas as POMC neurons.
Agouti-related peptide (AgRP) is an antagonist at MC3R and
MC4R (199) such that one action of these neurons is to counter
the activity of POMC neurons. NPY acts at Y receptors to stim-
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
ulate food intake (205–207). When either AgRP or NPY is administered chronically into the brain, body weight increases
(202, 208 –211). In fact, when a single dose of AgRP is administered into the brain near the ARC, food intake is increased for
1 wk or more (212, 213). Insulin and leptin each have a net effect
to suppress the activity of NPY/AgRP neurons in the ARC.
The POMC and NPY/AgRP neurons in the ARC share many
important features. Each is the origin of tracts projecting to other
hypothalamic and brain areas, the two tracts often occurring in
parallel. The POMC-originating tract has an overall catabolic
effect such that when it is more active food intake is reduced,
energy expenditure is increased, and if prolonged, body fat is lost.
Conversely, the NPY/AgRP-originating tract is anabolic, with
heightened activity causing more food to be ingested and body fat
to increase. Under normal conditions, both circuits are active
such that a change of input that is either stimulatory or inhibitory
to either type of neuron elicits rapid changes of many energetic
parameters. In the acute situation, both food intake and plasma
glucose are altered because the ARC influences circuits projecting to behavioral sites as well as autonomic circuits influencing
hepatic glucose secretion and pancreatic insulin secretion
(214 –216).
Another important aspect of the area including the ARC and
nearby hypothalamic nuclei is that receptors for many of the
satiation signals discussed above are expressed there; i.e. circulating ghrelin is thought to interact directly with ARC neurons
(152), which are also directly or indirectly sensitive to changes of
CCK, GLP-1, NMB, and apo A-IV. Because most of these peptides are made within the brain, the origin of molecules altering
ARC activity may not be directly from the plasma as occurs with
insulin, leptin, and ghrelin. Numerous circuits from the hindbrain satiation area and elsewhere in the brain project to the
region of the ARC (25, 27, 217). Finally, ARC neurons are also
sensitive to local levels of energy-rich nutrients, including glucose
(218), some long-chain fatty acids 关e.g. oleic acid (219, 220)兴,
and some amino acids 关e.g. leucine (221)兴.
Thus, the ARC is situated to be sensitive to a wide array of
signals important in energy regulation (216, 222–224). It is directly sensitive to hormones whose secretion is proportional to
body fat (insulin and leptin); it receives information on ongoing
meals either directly or indirectly; and it is sensitive to local levels
of nutrients. Importantly, numerous neuronal circuits interconnect the ARC and nearby hypothalamic areas with the nucleus of
the solitary tract, enabling the hypothalamic homeostatic network to be constantly aware of ongoing GI activity while at the
same time influencing brain stem autonomic areas projecting to
the GI tract, liver, pancreas, and other tissues (25, 27, 225–227).
The ARC can therefore be considered as a key afferent as well as
efferent area for the regulation of energy homeostasis.
Although ARC neurons project throughout the brain, two
nearby target areas are thought to be especially important. The
paraventricular nuclei (PVN) express both MC3R/MC4R and
various Y receptors, and PVN neurons in turn synthesize and
secrete neuropeptides that have a net catabolic action, including
CRH and oxytocin. Administration of exogenous CRH (228) or
oxytocin (229) into the brain reduces food intake. Hence, a catabolic circuit exists in which an increase of body fat is associated
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
with increased insulin and leptin, increased ␣MSH, and decreased NPY and AgRP activity, and consequently increased activity of CRH, oxytocin, and other catabolic signals; all of these
lead in turn to reduced food intake and increased energy
expenditure.
The lateral hypothalamic area (LHA) has a contrasting profile
from the PVN (230). It also receives direct inputs from the ARC,
and it contains neurons that synthesize and secrete anabolic peptides, including melanin-concentrating hormone and the orexins. Administration of melanin-concentrating hormone (231,
232) or orexin agonists (233) increases food intake and body
weight gain. The architecture and functioning of these opposing
hypothalamic circuits therefore enables rapid and fine-tuned
control over energy homeostasis because the brain can simultaneously turn up one system (e.g. catabolic or anabolic) while
turning down the other.
jcem.endojournals.org
S45
influencing not only when meals occur but how much food is
consumed as well. Only when extraneous factors are tightly controlled in laboratory animal experiments, or else when ingestion
is precisely monitored and quantified over periods of days or
weeks in free-feeding humans, do the effects of these homeostatic
signals become apparent.
Acknowledgments
Address all correspondence and requests for reprints to: Stephen C.
Woods, Department of Psychiatry, University of Cincinnati, 2170
East Galbraith Road, Cincinnati, Ohio 45237. E-mail: steve.woods@
psychiatry.uc.edu.
This work was supported by National Institutes of Health Awards
DK 17844 and DK 57900.
Disclosure Summary: S.C.W. received lecture fees from Sanofi-Aventis and from Merck. D.A.D. received lecture fees from Merck, Takeda,
and MannKind.
Integration of Satiation and Adiposity Signals
Total food intake each day is the sum of the intake in individual
meals (including snacks). As discussed above, the time that meals
are initiated is often under the control of nonhomeostatic influences (4, 5, 160, 234). Hence, whatever regulatory control exists
for body weight must be exerted on how much is eaten in individual meals, and meal termination is consequently under the
influence of satiation signals. The efficacy of satiation signals to
terminate a meal varies with the amount of fat in the body as
signaled to the brain by leptin and insulin. When an individual
has been food restricted (or been on a diet) and loses weight,
leptin and insulin secretion both decline, and a reduced adiposity
signal reaches the ARC. This in turn lowers sensitivity to satiation signals such as CCK, and the consequence is that more food
is eaten during meals before satiation or feeling full occurs. Conversely, individuals who have overeaten and gained weight have
elevated levels of adiposity signals and enhanced sensitivity to
satiation signals, reducing the trajectory of weight gain or even
promoting weight loss. When low doses of leptin or insulin are
infused directly into the brain near the ARC, they greatly enhance
the ability of satiation signals to reduce food intake 关e.g. much
less CCK or other satiation signals is required to terminate a meal
(235–241)兴, and when the adiposity signal in the brain is reduced,
satiation signals are less efficacious (242).
Conclusion
The brain receives and integrates diverse information pertinent
to the maintenance of energy homeostasis. Adiposity signals such
as insulin and leptin act in the arcuate nuclei to provide a background tone, and this tone in turn determines the sensitivity of
the brain to satiation signals influencing how much food is eaten
at any one time. It is important to recognize that this “homeostatic” mechanism provides at most a background influence, and
that it only subtly influences intake during any given meal. This
is because social factors, palatability, habits, the presence of
predators, stress, and many other factors are also always at work,
References
1. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central
nervous system control of food intake. Nature 404:661– 671
2. Woods SC, Seeley RJ, Porte Jr D, Schwartz MW 1998 Signals that regulate
food intake and energy homeostasis. Science 280:1378 –1383
3. Woods SC 2005 Signals that influence food intake and body weight. Physiol
Behav 86:709 –716
4. Strubbe JH, Woods SC 2004 The timing of meals. Psychol Rev 111:128 –141
5. Woods SC 1991 The eating paradox: how we tolerate food. Psychol Rev
98:488 –505
6. Woods SC, Ramsay DS 2007 Homeostasis: beyond Curt Richter. Appetite
49:388 –398
7. Moran TH, Kinzig KP 2004 Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol 286:G183–G188
8. Moran TH 2004 Gut peptides in the control of food intake: 30 years of ideas.
Physiol Behav 82:175–180
9. Strader AD, Woods SC 2005 Gastrointestinal hormones and food intake.
Gastroenterology 128:175–191
10. Polonsky KS, Given E, Carter V 1988 Twenty-four-hour profiles and pulsatile
patterns of insulin secretion in normal and obese subjects. J Clin Invest 81:
442– 448
11. Teff KL, Townsend RR 2004 Prolonged mild hyperglycemia induces vagally
mediated compensatory increase in C-peptide secretion in humans. J Clin
Endocrinol Metab 89:5606 –5613
12. Kaplan JM, Moran TH 2004 Gastrointestinal signaling in the control of food
intake. In: Stricker EM, Woods SC, eds. Handbook of behavioral neurobiology. Neurobiology of food and fluid intake. Vol. 4, no. 2. New York:
Kluwer Academic/Plenum Publishing; 273–303
13. Wren AM, Bloom SR 2007 Gut hormones and appetite control. Gastroenterology 132:2116 –2130
14. Wren AM 2008 Gut and hormones and obesity. Front Horm Res 36:165–181
15. Smith GP, Gibbs J 1992 The development and proof of the cholecystokinin
hypothesis of satiety. In: Dourish CT, Cooper SJ, Iversen SD, Iversen LL, eds.
Multiple cholecystokinin receptors in the CNS. Oxford, UK: Oxford University Press; 166 –182
16. Chandra R, Liddle RA 2007 Cholecystokinin. Curr Opin Endocrinol Diabetes Obes 14:63– 67
17. Grider JR 1994 Role of cholecystokinin in the regulation of gastrointestinal
motility. J Nutr 124:1334S–1339S
18. Raybould HE 2007 Mechanisms of CCK signaling from gut to brain. Curr
Opin Pharmacol 7:570 –574
19. Schwartz GJ, Moran TH, White WO, Ladenheim EE 1997 Relationships
between gastric motility and gastric vagal afferent responses to CCK and GRP
in rats differ. Am J Physiol 272:R1726 —R1733
20. Edwards GL, Ladenheim EE, Ritter RC 1986 Dorsomedial hindbrain participation in cholecystokinin-induced satiety. Am J Physiol 251:R971–R977
21. Lorenz DN, Goldman SA 1982 Vagal mediation of the cholecystokinin satiety effect in rats. Physiol Behav 29:599 – 604
S46
Woods and D’Alessio
Central Control of Body Weight and Appetite
22. Moran TH, Shnayder L, Hostetler AM, McHugh PR 1988 Pylorectomy reduces the satiety action of cholecystokinin. Am J Physiol 255:R1059 –R1063
23. Moran TH, Baldessarini AR, Salorio CF, Lowery T, Schwartz GJ 1997 Vagal
afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am J Physiol 272:R1245—R1251
24. Berthoud HR, Earle T, Zheng H, Patterson LM, Phifer C 2001 Food-related
gastrointestinal signals activate caudal brainstem neurons expressing both
NMDA and AMPA receptors. Brain Res 915:143–154
25. Berthoud HR 2007 Interactions between the “cognitive” and “metabolic”
brain in the control of food intake. Physiol Behav 91:486 – 498
26. Rinaman L 2004 Hindbrain contributions to anorexia. Am J Physiol Regul
Integr Comp Physiol 287:R1035—R1036
27. Rinaman L 2007 Visceral sensory inputs to the endocrine hypothalamus.
Front Neuroendocrinol 28:50 – 60
28. Rinaman L, Hoffman GE, Dohanics J, Le WW, Stricker EM, Verbalis JG
1995 Cholecystokinin activates catecholaminergic neurons in the caudal medulla that innervate the paraventricular nucleus of the hypothalamus in rats.
J Comp Neurol 360:246 –256
29. Beglinger C, Degen L, Matzinger D, D’Amato M, Drewe J 2001 Loxiglumide,
a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in
humans. Am J Physiol 280:R1149 –R1154
30. Hewson G, Leighton GE, Hill RG, Hughes J 1988 The cholecystokinin receptor antagonist L364,718 increases food intake in the rat by attenuation of
endogenous cholecystokinin. Br J Pharmacol 93:79 – 84
31. Reidelberger RD, O’Rourke MF 1989 Potent cholecystokinin antagonist
L-364,718 stimulates food intake in rats. Am J Physiol 257:R1512–R1518
32. Crawley JN, Beinfeld MC 1983 Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature 302:703–706
33. West DB, Fey D, Woods SC 1984 Cholecystokinin persistently suppresses
meal size but not food intake in free-feeding rats. Am J Physiol 246:
R776 —R787
34. Lieverse RJ, Jansen JB, Masclee AA, Lamers CB 1995 Satiety effects of a
physiological dose of cholecystokinin in humans. Gut 36:176 –179
35. Gutzwiller JP, Degen L, Matzinger D, Prestin S, Beglinger C 2004 Interaction
between GLP-1 and CCK-33 in inhibiting food intake and appetite in men.
Am J Physiol Regul Integr Comp Physiol 287:R562—R567
36. Lieverse RJ, Jansen JB, Masclee AA, Rovati LC, Lamers CB 1994 Effect of a
low dose of intraduodenal fat on satiety in humans: studies using the type A
cholecystokinin receptor antagonist loxiglumide. Gut 35:501–505
37. Degen L, Drewe J, Piccoli F, Grani K, Oesch S, Bunea R, D’Amato M, Beglinger C 2007 Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men. Am J Physiol Regul Integr Comp Physiol 292:R1391–R1399
38. Funakoshi A, Miyasaka K, Matsumoto H, Yamamori S, Takiguchi S,
Kataoka K, Takata Y, Matsusue K, Kono A, Shimokata H 2000 Gene structure of human cholecystokinin (CCK) type-A receptor: body fat content is
related to CCK type-A receptor gene promoter polymorphism. FEBS Lett
466:264 –266
39. Holst JJ 1997 Enteroglucagon. Annu Rev Physiol 59:257–271
40. Dube PE, Brubaker PL 2004 Nutrient, neural and endocrine control of glucagon-like peptide secretion. Horm Metab Res 36:755–760
41. Drucker DJ, Nauck MA 2006 The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet 368:1696 –1705
42. Giralt M, Vergara P 1999 Glucagonlike peptide-1 (GLP-1) participation in
ileal brake induced by intraluminal peptones in rat. Dig Dis Sci 44:322–329
43. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, Schmiegel
WH 1997 Glucagon-like peptide-1 inhibition of gastric emptying outweighs its
insulinotropic effects in healthy humans. Am J Physiol 273:E981–E988
44. Mentlein R 1999 Dipeptidyl-peptidase IV (CD26)–role in the inactivation of
regulatory peptides. Regul Pept 85:9 –24
45. Vahl TP, Paty BW, Fuller BD, Prigeon RL, D’Alessio DA 2003 Effects of
GLP-1-(7–36)NH2, GLP-1-(7–37), and GLP-1- (9 –36)NH2 on intravenous
glucose tolerance and glucose-induced insulin secretion in healthy humans.
J Clin Endocrinol Metab 88:1772–1779
46. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed
F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM,
Postic C, Burcelin R 2005 Brain glucagon-like peptide-1 increases insulin
secretion and muscle insulin resistance to favor hepatic glycogen storage.
J Clin Invest 115:3554 –3563
47. Knauf C, Cani PD, Kim DH, Iglesias MA, Chabo C, Waget A, Colom A,
Rastrelli S, Delzenne NM, Drucker DJ, Seeley RJ, Burcelin R 2008 Role of
central nervous system glucagon-like peptide-1 receptors in enteric glucosesensing. Diabetes, 57:2603–2612
48. Vahl TP, Tauchi M, Durler TS, Elfers EE, Fernandes TM, Bitner RD, Ellis KS,
Woods SC, Seeley RJ, Herman JP, D’Alessio DA 2007 Glucagon-like pep-
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
tide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 148:4965– 4973
Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Moller
M, Sheikh SP 1996 Central administration of GLP-1-(7–36) amide inhibits
food and water intake in rats. Am J Physiol 271:R848 –R856
Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ,
Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA,
Herbert J, Bloom SR 1996 A role for glucagon-like peptide-1 in the central
regulation of feeding 关see comments兴. Nature 379:69 –72
Donahey JC, van Dijk G, Woods SC, Seeley RJ 1998 Intraventricular GLP-1
reduces short- but not long-term food intake or body weight in lean and obese
rats. Brain Res 779:75– 83
Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM 1998 Glucagonlike peptide 1 increases the period of postprandial satiety and slows gastric
emptying in obese men. Am J Clin Nutr 68:525–530
Gutzwiller JP, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D,
Winterhalder R, Conen D, Beglinger C 1999 Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 44:81– 86
van Dijk G, Thiele TE, Donahey JCK, Campfield LA, Smith FJ, Burn P,
Bernstein IL, Woods SC, Seeley RJ 1996 Central infusion of leptin and GLP-1
(7–36) amide differentially stimulate c-Fos-like immunoreactivity in the rat
brain. Am J Physiol 271:R1096 –R1100
Shughrue PJ, Lane MV, Merchenthaler I 1996 Glucagon-like peptide-1
receptor (GLP1-R) mRNA in the rat hypothalamus. Endocrinology 137:
5159 –5162
Navarro M, Rodriquez de Fonseca F, Alvarez E, Chowen JA, Zueco JA,
Gomez R, Eng J, Blazquez E 1996 Colocalization of glucagon-like peptide-1
(GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in
rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an
inhibitory signal for food and water intake. J Neurochem 67:1982–1991
Kinzig KP, D’Alessio DA, Seeley RJ 2002 The diverse roles of specific GLP-1
receptors in the control of food intake and the response to visceral illness.
J Neurosci 22:10470 –10476
Larsen PJ, Tang-Christensen M, Jessop DS 1997 Central administration of
glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in
the rat. Endocrinology 138:4445– 4455
McMahon LR, Wellman PJ 1997 Decreased intake of a liquid diet in nonfood-deprived rats following intra-PVN injections of GLP-1 (7–36) amide.
Pharmacol Biochem Behav 58:673– 677
McMahon LR, Wellman PJ 1997 PVN infusion of GLP-1(7–36) amide suppresses feeding and drinking but does not induce conditioned taste aversions
or alter locomotion in rats. Am J Physiol 274:R23–R29
Seeley RJ, Blake K, Rushing PA, Benoit SC, Eng J, Woods SC, D’Alessio D
2000 The role of CNS GLP-1-(7–36) amide receptors in mediating the visceral
illness effects of lithium chloride. J Neurosci 20:1616 –1621
Kinzig KP, D’Alessio DA, Herman JP, Sakai RR, Vahl TP, Figueredo HF,
Murphy EK, Seeley RJ 2003 CNS glucagon-like peptide-1 receptors mediate
endocrine and anxiety responses to interoceptive and psychogenic stressors.
J Neurosci 23:6163– 6170
Naslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rossner
S, Hellstrom PM 1999 Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord
23:304 –311
Toft-Nielsen MB, Madsbad S, Holst JJ 1999 Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite
in type 2 diabetic patients. Diabetes Care 22:1137–1143
Gutzwiller JP, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger
C 1999 Glucagon-like peptide-1 promotes satiety and reduces food intake in
patients with diabetes mellitus type 2. Am J Physiol 276:R1541—R1544
Delgado-Aros S, Kim DY, Burton DD, Thomforde GM, Stephens D, Brinkmann
BH, Vella A, Camilleri M 2002 Effect of GLP-1 on gastric volume, emptying,
maximum volume ingested, and postprandial symptoms in humans. Am J
Physiol 282:G424 –G431
Kastin AJ, Akerstrom V, Pan W 2002 Interactions of glucagon-like peptide-1
(GLP-1) with the blood-brain barrier. J Mol Neurosci 18:7–14
Ahren B 2007 GLP-1-based therapy of type 2 diabetes: GLP-1 mimetics and
DPP-IV inhibitors. Curr Diab Rep 7:340 –347
Madsbad S, Krarup T, Deacon CF, Holst JJ 2008 Glucagon-like peptide
receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of
diabetes: a review of clinical trials. Curr Opin Clin Nutr Metab Care 11:
491– 499
Mafong DD, Henry RR 2008 Exenatide as a treatment for diabetes and
obesity: implications for cardiovascular risk reduction. Curr Atheroscler Rep
10:55– 60
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
71. Flatt PR, Bailey CJ, Green BD 2008 Dipeptidyl peptidase IV (DPP IV) and
related molecules in type 2 diabetes. Front Biosci 13:3648 –3660
72. Pei Z 2008 From the bench to the bedside: dipeptidyl peptidase IV inhibitors,
a new class of oral antihyperglycemic agents. Curr Opin Drug Discov Devel
11:512–532
73. Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M,
Taylor K 2007 Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type
2 diabetes. Diabetes Care 30:1487–1493
74. Kirkegaard P, Moody AJ, Holst JJ, Loud FB, Olsen PS, Christiansen J 1982
Glicentin inhibits gastric acid secretion in the rat. Nature 297:156 –157
75. Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA,
Bloom SR 2001 Oxyntomodulin inhibits food intake in the rat. Endocrinology 142:4244 – 4250
76. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M,
Ghatei MA, Bloom SR 2004 Peripheral oxyntomodulin reduces food intake
and body weight gain in rats. Endocrinology 145:2687–2695
77. Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR
2006 Oxyntomodulin increases energy expenditure in addition to decreasing
energy intake in overweight and obese humans: a randomised controlled trial.
Int J Obes (Lond) 30:1729 –1736
78. Wynne K, Bloom SR 2006 The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control. Nat Clin Pract Endocrinol
Metab 2:612– 620
79. Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR 2002 Repeated
ICV administration of oxyntomodulin causes a greater reduction in body
weight gain than in pair-fed rats. Am J Physiol Endocrinol Metab 283:
E1173—E1177
80. Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M,
Frost GS, Ghatei MA, Bloom SR 2003 Oxyntomodulin suppresses appetite
and reduces food intake in humans. J Clin Endocrinol Metab 88:4696 – 4701
81. Drucker DJ 1999 Glucagon-like peptide 2. Trends Endocrinol Metab 10:
153–156
82. Jeppesen PB 2003 Clinical significance of GLP-2 in short-bowel syndrome. J
Nutr 133:3721–3724
83. Orskov C, Holst JJ, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV 1986
Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon
gene, are secreted separately from pig small intestine but not pancreas. Endocrinology 119:1467–1475
84. Tang-Christensen M, Larsen PJ, Thulesen J, Romer J, Vrang N 2000 The
proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter
involved in the regulation of food intake. Nat Med 6:802– 807
85. Schmidt PT, Naslund E, Gryback P, Jacobsson H, Hartmann B, Holst JJ,
Hellstrom PM 2003 Peripheral administration of GLP-2 to humans has no
effect on gastric emptying or satiety. Regul Pept 116:21–25
86. Geary N 1998 Glucagon and the control of meal size. In: Smith GP, ed.
Satiation. From gut to brain. New York: Oxford University Press; 164 –197
87. Woods SC, Lutz TA, Geary N, Langhans W 2006 Pancreatic signals controlling food intake; insulin, glucagon, and amylin. Philos Trans R Soc Lond
B Biol Sci 361:1219 –1235
88. Woods SC, Lotter EC, McKay LD, Porte Jr D 1979 Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503–505
89. Geary N, Le Sauter J, Noh U 1993 Glucagon acts in the liver to control
spontaneous meal size in rats. Am J Physiol 264:R116 –R122
90. Langhans W, Zieger U, Scharrer E, Geary N 1982 Stimulation of feeding
in rats by intraperitoneal injection of antibodies to glucagon. Science
218:894 – 896
91. Le Sauter J, Noh U, Geary N 1991 Hepatic portal infusion of glucagon antibodies
increases spontaneous meal size in rats. Am J Physiol 261:R162–R165
92. Adrian TE, Bacarese-Hamilton AJ, Smith HA, Chohan P, Manolas KJ,
Bloom SR 1987 Distribution and postprandial release of porcine peptide YY.
J Endocrinol 113:11–14
93. Grandt D, Schimiczek M, Beglinger C, Layer P, Goebell H, Eysselein VE,
Reeve Jr JR 1994 Two molecular forms of peptide YY (PYY) are abundant
in human blood: characterization of a radioimmunoassay recognizing PYY
1–36 and PYY 3–36. Regul Pept 51:151–159
94. Mentlein R, Dahms P, Grandt D, Kruger R 1993 Proteolytic processing of
neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept 49:
133–144
95. Larhammar D 1996 Structural diversity of receptors for neuropeptide Y,
peptide YY and pancreatic polypeptide. Regul Pept 65:165–174
96. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL,
Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR 2002
jcem.endojournals.org
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
S47
Gut hormone PYY(3–36) physiologically inhibits food intake. Nature
418:650 – 654
Vincent RP, le Roux CW 2008 The satiety hormone peptide YY as a regulator
of appetite. J Clin Pathol 61:548 –552
Lin HC, Zhao XT, Wang L, Wong H 1996 Fat-induced ileal brake in the dog
depends on peptide YY. Gastroenterology 110:1491–1495
Pironi L, Stanghellini V, Miglioli M, Corinaldesi R, De Giorgio R, Ruggeri E,
Tosetti C, Poggioli G, Morselli Labate AM, Monetti N, Gozzetti G, Barbara L,
Go VLW 1993 Fat-induced ileal brake in humans: a dose-dependent phenomenon correlated to the plasma levels of peptide YY. Gastroenterology
105:733–739
Pfluger PT, Kampe J, Castaneda TR, Vahl T, D’Alessio DA, Kruthaupt T,
Benoit SC, Cuntz U, Rochlitz HJ, Moehlig M, Pfeiffer AF, Koebnick C,
Weickert MO, Otto B, Spranger J, Tschop MH 2007 Effect of human body
weight changes on circulating levels of peptide YY and peptide YY3–36.
J Clin Endocrinol Metab 92:583–588
Spiller RC, Trotman IF, Higgins BE, Ghatei MA, Grimble GK, Lee YC,
Bloom SR, Misiewicz JJ, Silk DB 1984 The ileal brake—inhibition of jejunal
motility after ileal fat perfusion in man. Gut 25:365–374
Nonaka N, Shioda S, Niehoff ML, Banks WA 2003 Characterization of
blood-brain barrier permeability to PYY3–36 in mouse. J Pharmacol Exp
Ther 306:948 –953
Batterham RL, Bloom SR 2003 The gut hormone peptide YY regulates appetite. Ann NY Acad Sci 994:162–168
Degen L, Oesch S, Casanova M, Graf S, Ketterer S, Drewe J, Beglinger C 2005
Effect of peptide YY3–36 on food intake in humans. Gastroenterology 129:
1430 –1436
le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM, Wynne KJ,
Kent A, Vincent RP, Gardiner J, Ghatei MA, Bloom SR 2006 Attenuated
peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 147:3– 8
Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS,
Ghatei MA, Bloom SR 2003 Inhibition of food intake in obese subjects by
peptide YY3–36. N Engl J Med 349:941–948
Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR, Chanoine
JP 2005 Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide,
and hunger responses to a mixed meal in anorexic, obese, and control female
adolescents. J Clin Endocrinol Metab 90:2161–2168
Lavebratt C, Alpman A, Persson B, Arner P, Hoffstedt J 2006 Common
neuropeptide Y2 receptor gene variant is protective against obesity among
Swedish men. Int J Obes (Lond) 30:453– 459
Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Collier JM, Hebert S,
Doelle H, Dent R, Pennacchio LA, McPherson R 2006 A PYY Q62P variant
linked to human obesity. Hum Mol Genet 15:387–391
Tso P, Liu M, Kalogeris TJ, Thomson AB 2001 The role of apolipoprotein
A-IV in the regulation of food intake. Annu Rev Nutr 21:231–254
Liu M, Doi T, Shen L, Woods SC, Seeley RJ, Zheng S, Jackman A, Tso P 2001
Intestinal satiety protein apolipoprotein AIV is synthesized and regulated in
rat hypothalamus. Am J Physiol 280:R1382–R1387
Fujimoto K, Fukagawa K, Sakata T, Tso P 1993 Suppression of food intake
by apolipoprotein A-IV is mediated through the central nervous system in
rats. J Clin Invest 91:1830 –1833
Fujimoto K, Machidori H, Iwakiri R, Yamamoto K, Fujisaki J, Sakata T, Tso
P 1993 Effect of intravenous administration of apolipoprotein A-IV on patterns of feeding, drinking and ambulatory activity in rats. Brain Res 608:
233–237
Lo CM, Zhang DM, Pearson K, Ma L, Sun W, Sakai RR, Davidson WS, Liu
M, Raybould HE, Woods SC, Tso P 2007 Interaction of apolipoprotein AIV
with cholecystokinin on the control of food intake. Am J Physiol Regul Integr
Comp Physiol 293:R1490 —R1494
Liu M, Shen L, Doi T, Woods SC, Seeley RJ, Tso P 2003 Neuropeptide Y and
lipid increase apolipoprotein AIV gene expression in rat hypothalamus. Brain
Res 971:232–238
Tso P, Liu M 2004 Apolipoprotein A-IV, food intake, and obesity. Physiol
Behav 83:631– 643
Okada S, York DA, Bray GA, Erlanson-Albertsson C 1991 Enterostatin
(Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake. Physiol Behav 49:1185–1189
Shargill NS, Tsuji S, Bray GA, Erlanson-Albertsson C 1991 Enterostatin
suppresses food intake following injection into the third ventricle of rats.
Brain Res 544:137–140
Mei J, Erlanson-Albertsson C 1992 Effect of enterostatin given intravenously and intracerebroventricularly on high-fat feeding in rats. Regul
Pept 41:209 –218
Okada S, York DA, Bray GA, Mei J, Erlanson-Albertsson C 1992 Differential
S48
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
Woods and D’Alessio
Central Control of Body Weight and Appetite
inhibition of fat intake in two strains of rat by the peptide enterostatin. Am J
Physiol 262:R1111–R1116
Muurahainen NE, Kissileff HR, Pi-Sunyer FX 1993 Intravenous infusion of
bombesin reduces food intake in humans. Am J Physiol 264:R350 –R354
Ladenheim EE, Wirth KE, Moran TH 1996 Receptor subtype mediation of
feeding suppression by bombesin-like peptides. Pharmacol Biochem Behav
54:705–711
Stein LJ, Woods SC 1982 Gastrin releasing peptide reduces meal size in rats.
Peptides 3:833– 835
Ladenheim EE, Hampton LL, Whitney AC, White WO, Battey JF, Moran TH
2002 Disruptions in feeding and body weight control in gastrin-releasing
peptide receptor deficient mice. J Endocrinol 174:273–281
Stuckey JA, Gibbs J, Smith GP 1985 Neural disconnection of gut from brain
blocks bombesin-induced satiety. Peptides 6:1249 –1252
Rushing PA, Henderson RP, Gibbs J 1998 Prolongation of the postprandial
intermeal interval by gastrin-releasing peptide 1–27 in spontaneously feeding
rats. Peptides 19:175–177
Lieverse RJ, Jansen JB, van de Zwan A, Samson L, Masclee AA, Rovati LC,
Lamers CB 1993 Bombesin reduces food intake in lean man by a cholecystokinin-independent mechanism. J Clin Endocrinol Metab 76:1495–1498
Gutzwiller JP, Drewe J, Hildebrand P, Rossi L, Lauper JZ, Beglinger C 1994
Effect of intravenous human gastrin-releasing peptide on food intake in humans. Gastroenterology 106:1168 –1173
Hildebrand P, Lehmann FS, Ketterer S, Christ AD, Stingelin T, Beltinger J,
Gibbons AH, Coy DH, Calam J, Larsen F, Beglinger C 2001 Regulation of
gastric function by endogenous gastrin releasing peptide in humans: studies
with a specific gastrin releasing peptide receptor antagonist. Gut 49:23–28
Degen LP, Peng F, Collet A, Rossi L, Ketterer S, Serrano Y, Larsen F, Beglinger
C, Hildebrand P 2001 Blockade of GRP receptors inhibits gastric emptying
and gallbladder contraction but accelerates small intestinal transit. Gastroenterology 120:361–368
Ludvik B, Kautzky-Willer A, Prager R, Thomaseth K, Pacini G 1997 Amylin:
history and overview. Diabet Med 14(Suppl 2):S9 –S13
Chance WT, Balasubramaniam A, Zhang FS, Wimalawansa SJ, Fischer JE
1991 Anorexia following the intrahypothalamic administration of amylin.
Brain Res 539:352–354
Lutz TA 2006 Amylinergic control of food intake. Physiol Behav 89:465– 471
Lutz TA, Del Prete E, Scharrer E 1994 Reduction of food intake in rats by
intraperitoneal injection of low doses of amylin. Physiol Behav 55:891– 895
Lutz TA, Geary N, Szabady MM, Del Prete E, Scharrer E 1995 Amylin
decreases meal size in rats. Physiol Behav 58:1197–1202
Rushing PA, Hagan MM, Seeley RJ, Lutz TA, Woods SC 2000 Amylin: a
novel action in the brain to reduce body weight. Endocrinology 141:850 – 853
Rushing PA, Hagan MM, Seeley RJ, Lutz TA, D’Alessio DA, Air EL, Woods
SC 2001 Inhibition of central amylin signaling increases food intake and body
adiposity in rats. Endocrinology 142:5035
Martinez A, Kapas S, Miller MJ, Ward Y, Cuttitta F 2000 Coexpression of
receptors for adrenomedullin, calcitonin gene-related peptide, and amylin in
pancreatic ␤-cells. Endocrinology 141:406 – 411
Christopoulos A, Christopoulos G, Morfis M, Udawela M, Laburthe M,
Couvineau A, Kuwasako K, Tilakaratne N, Sexton PM 2003 Novel receptor
partners and function of receptor activity-modifying proteins. J Biol Chem
278:3293–3297
Lutz TA, Senn M, Althaus J, Del Prete E, Ehrensperger F, Scharrer E 1998
Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates
the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in
rats. Peptides 19:309 –317
Rushing PA, Lutz TA, Seeley RJ, Woods SC 2000 Amylin and insulin interact
to reduce food intake in rats. Horm Metab Res 32:62– 65
Mollet A, Meier S, Grabler V, Gilg S, Scharrer E, Lutz TA 2003 Endogenous
amylin contributes to the anorectic effects of cholecystokinin and bombesin.
Peptides 24:91–98
Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG,
Weyer C, Kolterman OG 2002 A randomized study and open-label extension
evaluating the long-term efficacy of pramlintide as an adjunct to insulin
therapy in type 1 diabetes. Diabetes Care 25:724 –730
Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer
C, Kolterman OG 2003 Pramlintide as an adjunct to insulin therapy improves
long-term glycemic and weight control in patients with type 2 diabetes: a
1-year randomized controlled trial. Diabetes Care 26:784 –790
Wiedmer P, Nogueiras R, Broglio F, D’Alessio D, Tschop MH 2007 Ghrelin,
obesity and diabetes. Nat Clin Pract Endocrinol Metab 3:705–712
Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS
2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714 –1719
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
147. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S,
Fujimiya M, Niijima A, Fujino MA, Kasuga M 2001 Ghrelin is an appetitestimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345
148. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham
RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR 2001 Ghrelin causes hyperphagia and obesity in rats. Diabetes 50:2540 –2547
149. Tschöp M, Smiley DL, Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407:908 –913
150. Drazen DL, Vahl TP, D’Alessio DA, Seeley RJ, Woods SC 2006 Effects of a
fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 147:23–30
151. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS,
Schwartz MW, Basdevant A, Weigle DS 2002 Elevated plasma ghrelin levels
in Prader Willi syndrome. Nat Med 8:643– 644
152. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL,
Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura
LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S,
Colmers WF, Cone RD, Horvath TL 2003 The distribution and mechanism
of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit
regulating energy homeostasis. Neuron 37:649 – 661
153. Lawrence CB, Snape AC, Baudoin FM, Luckman SM 2002 Acute central
ghrelin and GH secretagogues induce feeding and activate brain appetite
centers. Endocrinology 143:155–162
154. Cummings DE 2006 Ghrelin and the short- and long-term regulation of
appetite and body weight. Physiol Behav 89:71– 84
155. Traebert M, Riediger T, Whitebread S, Scharrer E, Schmid HA 2002 Ghrelin
acts on leptin-responsive neurones in the rat arcuate nucleus. J Neuroendocrinol 14:580 –586
156. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H,
Kangawa K, Nakazato M 2002 The role of the gastric afferent vagal nerve in
ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120 –1128
157. Arnold M, Mura A, Langhans W, Geary N 2006 Gut vagal afferents are not
necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J Neurosci 26:11052–11060
158. Adolph EF 1947 Urges to eat and drink in rats. Am J Physiol 151:110 –125
159. Janowitz HD, Grossman MI 1949 Effect of variations in nutritive density of
food in dogs and rats. Am J Physiol 158:184 –193
160. Woods SC, Strubbe JH 1994 The psychobiology of meals. Psychon Bull Rev
1:141–155
161. McLaughlin CL, Baile CA 1979 Cholecystokinin, amphetamine and diazepam and feeding in lean and obese Zucker rats. Pharmacol Biochem Behav
10:87–93
162. Niederau C, Meereis-Schwanke K, Klonowski-Stumpe H, Herberg L 1997
CCK resistance in Zucker obese versus lean rats. Regul Pept 70:97–104
163. Kulkosky PJ, Breckenridge C, Krinsky R, Woods SC 1976 Satiety elicited by
the C-terminal octapeptide of cholecystokinin-pancreozymin in normal and
VMH-lesioned rats. Behav Biol 18:227–234
164. Chandler PC, Wauford PK, Oswald KD, Maldonado CR, Hagan MM 2004
Change in CCK-8 response after diet-induced obesity and MC3/4-receptor
blockade. Peptides 25:299 –306
165. Strohmayer AJ, Smith GP 1981 Cholecystokinin inhibits food intake in genetically obese (C57BL/6j-ob) mice. Peptides 2:39 – 43
166. Pi-Sunyer X, Kissileff HR, Thornton J, Smith GP 1982 C-terminal octapeptide of cholecystokinin decreases food intake in obese men. Physiol Behav
29:627– 630
167. Williams DL, Baskin DG, Schwartz MW 2006 Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes
55:3387–3393
168. West DB, Greenwood MRC, Marshall KA, Woods SC 1987 Lithium chloride, cholecystokinin and meal patterns: evidence the cholecystokinin suppresses meal size in rats without causing malaise. Appetite 8:221–227
169. West DB, Williams RH, Braget DJ, Woods SC 1982 Bombesin reduces food
intake of normal and hypothalamically obese rats and lowers body weight
when given chronically. Peptides 3:61– 67
170. D’Alessio DA, Vahl TP 2004 Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab 286:
E882—E890
171. D’Alessio DA, Vahl TP 2005 Utilizing the GLP-1 signaling system to treat
diabetes: sorting through the pharmacologic approaches. Curr Diab Rep
5:346 –352
172. Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs
DG, Wintle ME 2007 Metabolic effects of two years of exenatide treatment
on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes:
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
an interim analysis of data from the open-label, uncontrolled extension of
three double-blind, placebo-controlled trials. Clin Ther 29:139 –153
Poon T, Nelson P, Shen L, Mihm M, Taylor K, Fineman M, Kim D 2005
Exenatide improves glycemic control and reduces body weight in subjects
with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther 7:467– 477
Banks WA 2006 The blood-brain barrier as a regulatory interface in the
gut-brain axes. Physiol Behav 89:472– 476
Woods SC, Seeley RJ, Baskin DG, Schwartz MW 2003 Insulin and the bloodbrain barrier. Curr Pharm Des 9:795– 800
Benoit SC, Clegg DJ, Seeley RJ, Woods SC 2004 Insulin and leptin as adiposity signals. Recent Prog Horm Res 59:267–285
Friedman JM 2002 The function of leptin in nutrition, weight, and physiology. Nutr Rev 60:S1–S14; discussion S68- 84:85– 87
Seeley RJ, Woods SC 2003 Monitoring of stored and available fuel by the
CNS: implications for obesity. Nat Rev Neurosci 4:901–909
Grossman SP 1986 The role of glucose, insulin and glucagon in the regulation
of food intake and body weight. Neurosci Biobehav Rev 10:295–315
Langhans W 1996 Metabolic and glucostatic control of feeding. Proc Nutr
Soc 55:497–515
Lotter EC, Woods SC 1977 Injections of insulin and changes of body weight.
Physiol Behav 18:293–297
Nicolaidis S, Rowland N 1976 Metering of intravenous versus oral nutrients
and regulation of energy balance. Am J Physiol 231:661– 668
Vanderweele DA, Haraczkiewicz E, Van Itallie TB 1982 Elevated insulin and
satiety in obese and normal weight rats. Appetite 3:99 –109
Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W 2004
Intranasal insulin reduces body fat in men but not in women. Diabetes 53:
3024 –3029
Hallschmid M, Benedict C, Born J, Fehm HL, Kern W 2004 Manipulating
central nervous mechanisms of food intake and body weight regulation by
intranasal administration of neuropeptides in man. Physiol Behav 83:55– 64
Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS 2006 Recombinant methionyl human leptin therapy in replacement doses improves insulin
resistance and metabolic profile in patients with lipoatrophy and metabolic
syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab 91:2605–2611
Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P 2005
Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 54:1994 –2002
Israel PA, Park CR, Schwartz MW, Green PK, Sipols AJ, Woods SC, Porte Jr
D, Figewicz DP 1993 Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat. Brain Res Bull 30:571–575
Owen OE, Reichard GAJ, Boden G, Shuman C 1974 Comparative measurements of glucose, ␤-hydroxybutyrate, acetoacetate, and insulin in blood and
cerebrospinal fluid during starvation. Metabolism 23:7–14
Stein LJ, Dorsa DM, Baskin DG, Figlewicz DP, Ikeda H, Frankmann SP,
Greenwood MR, Porte Jr D, Woods SC 1983 Immunoreactive insulin levels
are elevated in the cerebrospinal fluid of genetically obese Zucker rats. Endocrinology 113:2299 –2301
Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MRC, Porte Jr D,
Woods SC 1986 Intraventricular insulin reduces food intake and body weight
of lean but not obese Zucker rats. Appetite 7:381–386
Woods SC, D’Alessio DA, Tso P, Rushing PA, Clegg DJ, Benoit SC, Gotoh
K, Liu M, Seeley RJ 2004 Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiol Behav 83:573–578
Cota D, Matter EK, Woods SC, Seeley RJ 2008 The role of hypothalamic
mTORC1 signaling in diet-induced obesity. J Neurosci 28:7202–7208
Air EL, Strowski MZ, Benoit SC, Conarello SL, Salituro GM, Guan XM, Liu K,
Woods SC, Zhang BB 2002 Small molecule insulin mimetics reduce food intake
and body weight and prevent development of obesity. Nat Med 8:179 –183
Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez
MT, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR,
Heck JV, Smith RG, Moller DE 1999 Discovery of a small molecule insulin
mimetic with antidiabetic activity in mice. Science 284:974 –977
Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ 2001 The
arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25(Suppl 5):S63—S67
Peruzzo B, Pastor FE, Blazquez JL, Schobitz K, Pelaez B, Amat P, Rodriguez
EM 2000 A second look at the barriers of the medial basal hypothalamus. Exp
Brain Res 132:10 –26
Ahima RS, Saper CB, Flier JS, Elmquist JK 2000 Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 21:263–307
Cone RD 2005 Anatomy and regulation of the central melanocortin system.
Nat Neurosci 8:571–578
Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB 2005 Identi-
jcem.endojournals.org
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
S49
fying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 493:63–71
Schwartz MW, Porte Jr D 2005 Diabetes, obesity, and the brain. Science
307:375–379
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW 2006
Central nervous system control of food intake and body weight. Nature
443:289 –295
Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ,
Woods SC 2002 The catabolic action of insulin in the brain is mediated by
melanocortins. J Neurosci 22:9048 –9052
Seeley R, Yagaloff K, Fisher S, Burn P, Thiele T, van DG, Baskin D, Schwartz
M 1997 Melanocortin receptors in leptin effects. Nature 390:349
Stanley BG, Leibowitz SF 1984 Neuropeptide Y: stimulation of feeding
and drinking by injection into the paraventricular nucleus. Life Sciences
35:2635–2642
Clark JT, Kalra PS, Crowley WR, Kalra SP 1984 Neuropeptide Y and human
pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology
115:427– 429
Corp ES, Melville LD, Greenberg D, Gibbs J, Smith GP 1990 Effect of fourth
ventricular neuropeptide Y and peptide YY on ingestive and other behaviors.
Am J Physiol 259:R317–R323
Zarjevski N, Cusin I, Vetter R, Rohner-Jeanrenaud F, Jeanrenaud B 1993
Chronic intracerebroventricular neuropeptide-Y administration to normal
rats mimics hormonal and metabolic changes of obesity. Endocrinology 133:
1753–1758
Wilson BD, Ollmann MM, Barsh GS 1999 The role of agouti-related protein
in regulating body weight. Mol Med Today 5:250 –256
Vettor R, Zarjevski N, Cusin I, Johner-Jeanrenaud F, Jeanrenaud B 1994
Induction and reversibility of an obesity syndrome by intracerebroventricular
neuropeptide Y administration to normal rats. Diabetologia 37:1202–1208
Ollmann M, Wilson B, Yang Y, Kerns J, Chen Y, Gantz I, Barsh G 1997
Antagonism of central melanocortin receptors in vitro and in vivo by agoutirelated protein. Science 278:135–138
Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der
Ploeg HT, Woods SC, Seeley RJ 2000 Long-term orexigenic effects of AgRP(83–132) involve mechanisms other than melanocortin receptor blockade.
Am J Physiol 279:R47–R52
Hagan MM, Benoit SC, Rushing PA, Pritchard LM, Woods SC, Seeley RJ
2001 Immediate and prolonged patterns of agouti-related peptide-(83–132)induced c-Fos activation in hypothalamic and extrahypothalamic sites. Endocrinology 142:1050 –1056
Porte Jr D, Baskin DG, Schwartz MW 2005 Insulin signaling in the central
nervous system: a critical role in metabolic homeostasis and disease from C.
elegans to humans. Diabetes 54:1264 –1276
Schwartz MW 2006 Central nervous system regulation of food intake. Obesity (Silver Spring) 14(Suppl 1):1S– 8S
Woods SC, Seeley RJ, Cota D 2008 Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr 28:295–311
Berthoud HR 2002 Multiple neural systems controlling food intake and body
weight. Neurosci Biobehav Rev 26:393– 428
Levin BE 2006 Metabolic sensing neurons and the control of energy homeostasis. Physiol Behav 89:486 – 489
Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L,
Schwartz GJ, Rossetti L 2005 Hypothalamic sensing of circulating fatty acids
is required for glucose homeostasis. Nat Med 11:320 –327
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L 2002 Central
administration of oleic acid inhibits glucose production and food intake.
Diabetes 51:271–275
Cota D, Proulx K, Woods SC, Seeley RJ 2006 Role of leucine in regulating
food intake. Science 313:1236 –1238
Cota D, Proulx K, Seeley RJ 2007 The role of CNS fuel sensing in energy and
glucose regulation. Gastroenterology 132:2158 –2168
Seeley RJ, York DA 2005 Fuel sensing and the central nervous system (CNS):
implications for the regulation of energy balance and the treatment for obesity. Obes Rev 6:259 –265
Fehm HL, Kern W, Peters A 2006 The selfish brain: competition for energy
resources. Prog Brain Res 153:129 –140
Berthoud HR 2006 Homeostatic and non-homeostatic pathways involved in
the control of food intake and energy balance. Obesity (Silver Spring)
14(Suppl 5):197S–200S
Grill HJ, Kaplan JM 2002 The neuroanatomical axis for control of energy
balance. Front Neuroendocrinol 23:2– 40
Schwartz GJ 2006 Integrative capacity of the caudal brainstem in the control
of food intake. Philos Trans R Soc Lond B Biol Sci 361:1275–1280
Richard D, Huang Q, Timofeeva E 2000 The corticotropin-releasing hor-
S50
229.
230.
231.
232.
233.
234.
235.
Woods and D’Alessio
Central Control of Body Weight and Appetite
mone system in the regulation of energy balance in obesity. Int J Obes Relat
Metab Disord 24:S36 —S39
Verbalis JG, Blackburn RE, Olson BR, Stricker EM 1993 Central oxytocin
inhibition of food and salt ingestion: a mechanism for intake regulation of
solute homeostasis. Regul Pept 45:149 –154
Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T 1998 Hypocretin/orexinand melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y
and agouti gene-related protein systems. J Comp Neurol 402:460 – 474
Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ,
Mathes WF, Przypek R, Kanarek R, Maratos-Flier E 1996 A role for melaninconcentrating hormone in the central regulation of feeding behaviour. Nature
380:243–247
Nahon JL 2006 The melanocortins and melanin-concentrating hormone in
the central regulation of feeding behavior and energy homeostasis. C R Biol
329:623– 638; discussion 653– 655
Sweet DC, Levine AS, Billington CJ, Kotz CM 1999 Feeding response to
central orexins. Brain Res 821:535–538
Strubbe JH, van Dijk G 2002 The temporal organization of ingestive behaviour and its interaction with regulation of energy balance. Neurosci Biobehav
Rev 26:485– 498
Matson CA, Wiater MF, Kuijper JL, Weigle DS 1997 Synergy between
J Clin Endocrinol Metab, November 2008, 93(11):S37–S50
236.
237.
238.
239.
240.
241.
242.
243.
leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides
18:1275–1278
Matson CA, Ritter RC 1999 Long-term CCK-leptin synergy suggests a role
for CCK in the regulation of body weight. Am J Physiol 276:R1038 –R1045
Riedy CA, Chavez M, Figlewicz DP, Woods SC 1995 Central insulin enhances sensitivity to cholecystokinin. Physiol Behav 58:755–760
Emond M, Schwartz GJ, Ladenheim EE, Moran TH 1999 Central leptin
modulates behavioral and neural responsivity to CCK. Am J Physiol 276:
R1545–R1549
Figlewicz DP, Stein LJ, West D, Porte Jr D, Woods SC 1986 Intracisternal
insulin alters sensitivity to CCK-induced meal suppression in baboons. Am J
Physiol 250:R856 –R860
Ladenheim EE, Emond M, Moran TH 2005 Leptin enhances feeding suppression and neural activation produced by systemically administered bombesin. Am J Physiol Regul Integr Comp Physiol 289:R473–R477
Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes
CJ, Baskin DG, Schwartz MW 2005 Leptin action in the forebrain regulates
the hindbrain response to satiety signals. J Clin Invest 115:703–710
McMinn JE, Sindelar DK, Havel PJ, Schwartz MW 2000 Leptin deficiency
induced by fasting impairs the satiety response to cholecystokinin. Endocrinology 141:4442– 4448
Grill HJ, Smith GP 1988 Cholecystokinin decreases sucrose intake in chronic
decerebrate rats. Am J Physiol 254:R853–R856