The Control of Food Intake: Behavioral vs Molecular Perspectives

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Cell Metab. Author manuscript; available in PMC 2011 May 10.
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Cell Metab. 2009 June ; 9(6): 489–498. doi:10.1016/j.cmet.2009.04.007.
The Control of Food Intake: Behavioral versus Molecular

Perspectives
Stephen C. Woods1,*
1 Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45237, USA
Abstract
To meet the continuous demand for energy, organisms use diverse signals to match food intake
with energy needs. This paper reviews the effect of satiation signals and adiposity signals on food
intake, including how they interact in the brain and how their influence changes with experience.
Whereas meal initiation is influenced by external environmental factors, meal size is influenced by
an array of signals that can be partitioned according to their reliability in indicating caloric content
of food. It is argued that the malleability of satiation signals renders them poor candidates as
pharmacological targets to control body weight.
Introduction
Rapid advances in understanding cell biology and in unraveling the complex neurocircuitry
of the brain have led to a wealth of novel findings on the molecular and neural control of
food intake and energy homeostasis, and one consequence is that important intersections
have arisen among scholars interested in ingestive behavior, neuroscience, cell and
molecular biology, and genetics. The accelerating pace at which this is occurring makes it
imperative that occasional pauses be interspersed so that new information and its
implications can be appropriately interpreted and assimilated. I herein review what is known
of the factors that contribute to the control of food intake, emphasizing areas where
interpretations based on molecular biology versus those based on behavioral science may
lead to different conclusions, as well as the implications for therapy and where research
should be directed.
Energy Homeostasis
The brain is a key player in the control of energy homeostasis (Elmquist et al., 2005; Flier,
2004; Schwartz et al., 2000). It receives a continuous stream of diverse signals regarding
energy status throughout the body and consequently influences energy consumption as well
as the entry of nutrients into the blood and their utilization by most tissues (Figure 1). The
brain integrates incoming information in the form of hormonal and neural signals with data
on energetic needs or anticipated needs, with environmental factors such as where and when
food might be available, with aspects of the social situation, with memory for past
experiences, with hedonic factors, and with many others, as well.
An important role of the brain is to ensure adequate circulating energy for immediate tissue
needs as well as adequate stored energy to weather intervals when external energy is scarce
(Seeley and Woods, 2003). Finding and ingesting food are consequently tightly coordinated
with the control of plasma glucose, fatty acids, and other nutrients. Under most
circumstances, the levels of energy-rich fuels in the blood are relatively constant, with use
*
Correspondence: steve.woods@psychiatry.uc.edu.
Woods Page 2
by tissues matched well to secretion by liver and adipocytes. Meals constitute an exception
as newly digested nutrients enter the blood, raising plasma glucose and other nutrients
considerably above basal levels, and these in turn generate signals that are relayed to the
brain (Friedman, 1998). An important consideration of the brain is to limit meal size, thus
precluding especially large perturbations of plasma nutrients (Woods, 1991; Woods and
Ramsay, 2007). This is accomplished in part by accurately anticipating meals and
subsequently coordinating ongoing information about calories being consumed (via satiation
signals), the levels of fuels already in the plasma (via direct sensing by specialized cells in
the brain and elsewhere), and the amount of energy present in various storage depots (via
adiposity signals). In sum, a key function of the brain is to coordinate diverse processes that
allow optimal circulating and storage levels of energy-rich nutrients.
Satiation Signals
Satiation signals arise during meals and limit meal size (Moran, 2004; Strader and Woods,
2005). The best known is the duodenal peptide cholecystokinin (CCK), which is secreted in
proportion to lipids and proteins in the meal and which stimulates receptors on nearby vagal
axons (Raybould, 2007). The signal is relayed neurally to the hindbrain and onto diverse
brain areas, including the hypothalamus and reward areas. Most satiation signals follow a
similar pattern as CCK, either stimulating sensory nerves passing to the hindbrain or else
stimulating the hindbrain directly. The signals are integrated in the hindbrain, and digestive
reflexes influencing gastrointestinal activity are coordinated and initiated. Satiation signals
are also relayed to other brain areas, where they are integrated with adiposity signals, with
hedonic and social factors, and with local levels of nutrients (Berthoud, 2007). The net effect
is that as satiation signals are generated during a meal, their impact gradually accumulates,
ultimately activating circuits that cause individuals to stop eating. This is true even when
ample food remains and more could be eaten, in part to prevent extreme postprandial
elevations of plasma fuels (Woods, 1991).
Exogenous administration of compounds that stimulate the receptors for endogenous

satiation factors cause people or animals to respond as if additional extra calories have been
consumed; i.e., they cease eating prematurely and consequently eat less than otherwise.
Analogously, when the activity of endogenous satiation factors is experimentally reduced,
larger meals are consumed (Moran, 2004; Strader and Woods, 2005). The important point is
that when the activity of CCK and/or other satiation signals is manipulated in either
direction, the size of the ongoing meal is altered. This is an acute, within-meal phenomenon,
and its relevance to more chronic situations and to body weight is discussed below. It is
noteworthy that administering CCK prior to the start of a meal does not delay the onset of
eating, but rather reduces the amount consumed once eating begins (Moran, 2004; Smith and
Gibbs, 1992).
The reliability with which meal size can be acutely manipulated makes it tempting to
consider whether satiation factors have therapeutic potential to control body weight; i.e., can
formulations of drugs that act on receptors for CCK or any other satiation factor be
developed so that the size of every meal is reduced? A first-order answer is that if
individuals are coerced to eat smaller meals, they will compensate and defend their body
weight by eating more often, and this has been observed when CCK is administered prior to
every meal; i.e., animals eat smaller and more frequent meals while keeping body weight
constant (West et al., 1984). That said, long-acting formulations of some compounds that
reduce meal size when given acutely (e.g., long-acting GLP-1 [D’Alessio and Vahl, 2005])
do result in weight loss (Buse et al., 2007), but it is not clear that the chronic effect is due to
continued hypophagia as opposed to other, nonbehavioral actions of the compounds (Woods
and D’Alessio, 2008). Pertinent to this, genetically altered animals that uniquely lack CCK

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(Lo et al., 2008) have normal food intake and body weight, suggesting that CCK is not
necessary for normal homeostatic regulation. Further, as discussed below, the ability of
satiation factors to influence meal size is plastic and subject to change based on experience.
To summarize, satiation signals inform the brain of the quantity and quality of food being
eaten, and the brain incorporates this information into a complex interaction with other
factors in deciding when to stop the meal.
Adiposity Signals
Adiposity signals, hormones secreted in proportion to body fat that influence the activity of
the brain and other tissues, include insulin and leptin (Myers et al., 2007). A higher level of
either in the blood is indicative of more stored fat. Each is transported through brain
capillaries to gain access to receptors on neurons in the hypothalamus, the hindbrain, and
elsewhere (Banks, 2006; Woods et al., 2003). When either insulin or leptin is delivered in a
way that increases its activity in the brain, less food is consumed, and when the action of
either hormone in the brain is reduced, food intake increases (Schwartz et al., 2000; Woods
et al., 1998). Unlike what occurs with satiation signals, chronically changing insulin or
leptin activity locally in the hypothalamus changes body weight as well. Animals respond to
changes in the activity of adiposity signals as if the amount of fat in their bodies had
changed; i.e., they alter food intake and consequently change body fat. The conundrum is
that whereas administering adiposity signals to normal-weight individuals reduces food
intake and body fat, obese individuals are relatively resistant; i.e., while the obese state is
characterized by hyperinsulinemia and hyperleptinemia, it is also characterized by insulin
and leptin resistance. One consequence is that chronically administering these compounds,
at least systemically, causes little or no loss of weight in obese humans, and chronic insulin
can actually increase body weight as intermittent hypoglycemia can elicit persistent
overeating (Langhans, 1996).
It should not be inferred that insulin and leptin are either interchangeable or exhaustive as
adiposity signals. Each has multiple unique actions throughout the body, and they also differ
as adiposity signals. Leptin is disproportionately secreted from subcutaneous fat, whereas
insulin secretion reflects mainly visceral fat (Bjorntorp, 1997). Females, whether rodents or
humans, have proportionally more subcutaneous and less visceral fat than males (Dusserre et
al., 2000), and females have higher plasma leptin and lower plasma insulin than comparably
obese males (Clegg et al., 2006). This dichotomy is also manifest in the brain, females being
relatively more sensitive to the anorexigenic action of leptin and males more sensitive to
insulin (Clegg et al., 2003, 2006), the difference due in part to estrogen action locally in the
hypothalamus (Musatov et al., 2007). In some hypothalamic areas, insulin and leptin
activate overlapping enzymatic cascades (Air et al., 2002; Niswender and Schwartz, 2003),
and the anorexigenic action of each can be blocked, for example, by inhibitors of PI3 kinase
or melanocortin 3/4 receptor antagonists (Benoit et al., 2002; Seeley et al., 1997). Hence,
while insulin and leptin have many differential actions, they also stimulate common
pathways, resulting in reduced food intake and weight loss.
Other hormones are secreted in proportion to body fat and may serve as adiposity signals.
Amylin is cosecreted with insulin, and its levels are directly proportional to visceral fat
(Cooper, 1994). Amylin reduces food intake and body weight by acting at receptors in the
hindbrain, and administration of antagonists that block amylin action increase food intake
(Lutz, 2006). Amylin functions both as a satiation signal, reducing meal size, and as an
adiposity signal, influencing body weight (Lutz, 2006). Adiponectin is secreted from fat
cells in inverse proportion to fat mass (Wang and Scherer, 2008). Although adiponectin has
not been reported to alter food intake, it does increase energy expenditure via a central
mechanism (Qi et al., 2004). Thus, several peripherally originating hormones are

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proportional to adipose tissue stores, all gain access to receptors in the brain, and all exert a
central influence over energy homeostasis. Insulin and leptin provide useful examples, since
they have been most investigated in this regard.
Factors that Influence Meal Size

Determining when and how much to eat are key challenges of the brain. An organism living
in a stable environment with ample available food has the luxury of establishing regular
eating patterns and optimally integrating caloric intake with other behaviors (Strubbe and
Woods, 2004). It can optimize the amount of energy to store as well as how much to eat in
individual meals spread over the day. Because its food supply is consistent and reliable, it
learns to make responses to take in and process the energy most efficiently (Woods, 1991).
Temporal cues dictate the optimal times to eat in relation to other behaviors. Odors and
tastes become reliable bellwethers of food quality and energy content, and these relatively
distal cues acquire the ability to guide food taking behavior (i.e., how much to eat of a
particular food). They are distal cues in the sense that while their presence has been
associated with energy content in the past, they have no energy content themselves (Figure
2). In a less predictable environment, the association between distal cues and actual energy
content can be tenuous, requiring the individual to rely to a greater extent upon more
proximal cues: i.e., with cues more closely tied to actual caloric content. Signals such as
CCK are intermediate cues, being secreted in response to a physicochemical analysis of
ingested food by intestinal cells. In a stable environment, in which the food is constant, a
certain level of CCK activity or of gastric distension accurately presages the number of
calories that can be anticipated to enter the blood from the intestines over the next hour or
so; nonetheless, activity of CCK or any other “satiation” signal is not necessarily hard-wired
to caloric content. The ultimate proximal cues are glucose, fatty acids or other energy-rich
molecules reaching a sensory cell, or else the consequences of their intracellular metabolism
(i.e., metabolites, altered enzyme activity). The point is that there is an energy-reliability
gradient that maps onto cues an individual can use to guide energy intake. In a highly
predictable world, distal cues habitually dictate when meals should end.
This continuum also correlates with time until ingested nutrients enter the blood. An
individual using taste or other oral cues can stop eating long before most nutrients are
digested and absorbed with the assurance that sufficient but not excessive calories have been
gained. As it shifts to using more proximal cues, the lag between ingestion and its
consequences lessens. Controlling intake via distal cues bestows the advantage of being able
to eat relatively large meals because appropriate anticipatory responses can be made
sufficiently far in advance to lessen the meal’s metabolic impact. Anticipatory responses
made prior to the actual ingestion of food, such as the secretion of cephalic insulin, reduce
the prandial increase of glucose and other nutrients that would otherwise occur (Woods,
1991).
Having to rely upon more proximal cues comes at a cost of risking consuming too many
calories at once or else adopting a pattern of eating smaller and more frequent meals, thus
perhaps interfering with other behaviors (Woods, 1991; Woods and Ramsay, 2007). The
point is that myriad cues may be available to assist in the decision as to when to stop a meal.
Distal cues are preferred so long as they reliably predict nutrients, and individuals easily
learn to rely upon them. However, in a variable world, individuals revert to cues more
closely tied to actual nutrient content. As a common example, animals use taste to guide
intake when food is consistent; however, when taste is experimentally dissociated from
caloric content, animals abandon it as a cue in deciding when to end a meal (Sclafani, 2006).
Analogously, when confronted with novel-tasting food (i.e., food with no previous gustatory
associations), individuals are neophobic, eating very little until their more proximal nutrient

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sensors have a chance to experience and certify the consequences (Rozin, 1968). Similarly,
when caloric content is experimentally dissociated from CCK activity, the ability of CCK to
reduce meal size becomes attenuated (Duncan et al., 2005; Goodison and Siegel, 1995).
Numerous considerations enter into the determination as to when and how much to eat.
When to eat is largely dictated by environmental factors, especially time of day. How much
to eat once a meal is underway is governed by a potentially broad array of satiation signals.
In a predictable world, individuals learn to utilize signals farther and farther from actual
energy content, enabling the consumption of large meals with little metabolic perturbation.
In more variable worlds, more proximal cues come into play at the expense of eating smaller
meals, requiring the individual to eat more often to meet its energy requirements.
Models of Satiation
Satiation signals could work in many different ways. There may be a satiation threshold
such that when an integrated signal (e.g., combinations of taste, gastric distension, CCK,
etc.) reaches a certain level of intensity, eating stops (Figure 3). Such a model is implicitly
assumed in many experiments, where an administered satiation signal is presumed to push
the balance of already-present factors over the stop-eating threshold. While certainly
possible, especially if the threshold increases or decreases with body fat, the model
nonetheless seems maladaptive, as it could unduly constrain behavior. Thresholds imply a
degree of certainty, yet as discussed below, the evidence suggests that satiation signals act in
a more probabilistic manner.
A different model assumes that the sensory inputs that guide eating follow the same
principles as those in other sensory systems. Intrinsic signals that influence the start or finish
of meals are always present at some level (e.g., there are always, albeit low, basal levels of
CCK; and stomach distension is always monitored by the brain), but these signals generally
go unheeded unless other factors intervene. Just as occurs for most sensory systems (e.g.,
olfaction), adaptation occurs until other inputs cause the brain to attend and focus on
already-present signals. With regard to satiation, the behavioral act of eating could sensitize
brain circuits responsive to CCK and other signals generated during meals, thereby shifting
attention to relevant circuits constantly active but normally off the radar screen. Likewise,
when to initiate eating would also depend on extrinsic factors causing the brain to focus
upon already-present signals. Time of day is one such extrinsic factor. Individuals eat at a
particular time because they are accustomed to eat at that time and have learned to make
anticipatory responses to cope with the caloric load at that time (Strubbe and Woods, 2004).
One consequence is that if always-present signals such as blood glucose, stomach
distension, or any other hypothesized “hunger” signal changes at that time as a result of
making meal-anticipatory responses, the change can as easily be attributed to knowing a

meal is imminent as to a biological need for energy. The point is that anticipating eating,
even at a subconscious level, elicits a broad array of endocrine and gastrointestinal changes
that are themselves detected and associated with eating. In this schema, rather than a need
for energy causing a threshold to be crossed and triggering changes that are then perceived
and interpreted as “hunger,” under most circumstances the perception of hunger arises
secondarily to the reality that eating normally occurs in that situation.
Behaviors that serve other regulatory systems are analogous to eating. We become sleepy at
times we usually go to sleep and wake up at around the same time most days. Certainly
other factors intervene. The more chronically deprived one is (of food, sleep, or whatever),
the more likely extrinsic signals are to trigger behavior, in part because activity in the
appropriate circuits is more intense. When to urinate provides a common example. Neural
signals constantly indicate bladder distension, increasing in magnitude gradually as urine

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accumulates. If they get especially high, the absolute intensity may be sufficient to appear
on the conscious radar screen. Prior to that extreme, the slowly changing signals go
unheeded unless an extrinsic factor focuses attention on them. For example, some people,
when riding in a car and spying a service station, experience an urge to urinate. Rather than
their bladder suddenly filling to threshold, an external cue focuses attention on already
present signals. The feeling of urgency is real and can be alleviated either by reducing the
signal (i.e., urinating) or else by focusing attention elsewhere. In an analogous fashion, some
individuals, due to past associations, are especially sensitive to blood glucose, stomach
distension, or any other parameter that varies systematically over time since the previous
meal or with food deprivation, and some other factor is necessary to enable these always-
present messages to be gated through to circuits controlling behavior. These individuals thus
detect changes in internal parameters that occur as a consequence of the brain preparing for
an impending meal and interpret those changes as “hunger.”
Control of Meal Onset and Meal Size

Meal size is more tightly controlled by homeostatic processes than meal onset because the
specific time(s) at which humans initiate meals is/are largely dictated by factors outside
those being considered here; i.e., we eat at times convenient for our schedules or because
unexpected food becomes available (Strubbe and Woods, 2004). Opportunistic examples of
eating, if they become habitual and predictable, fall under the same controls as those
discussed above. They also highlight the importance of satiation signals in limiting
individual meal size in order to keep daily caloric intake somewhat constant; i.e., since the
times that meals occur as well as the number of meals per day may be variable, controlling
meal size is an effective strategy for maintaining body weight.
An important goal of experiments evaluating factors that influence food intake is to

minimize variance. To that end, subjects are first adapted to the laboratory environment in
which light cycle, temperature, and food quality are standardized, consistent, and well
controlled. Animals are housed individually to preclude social interactions. In this setting,
time of day becomes a potent determinant of meal time, with the two largest meals occurring
at the most predictable times; i.e., lights out and lights on (Kissileff, 1970). Laboratory rats
and mice develop highly regular, individualized 24 hr eating patterns. Because the food (lab
chow or some alternative specified diet) is the same at every meal, taste, mouth-feel,
stomach distension, gastrointestinal secretions, and so on are all excellent correlates of
ingested calories; i.e., distal cues become as reliable as intermediate or proximal cues in
guiding behavior, for all have equivalent predictive power. What varies is the robustness of
the link to caloric content.
The observation that one or another factor reliably reduces intake in an acute feeding test
should not be taken as evidence that it would persist under chronic conditions. In fact, every
time a compound is administered that mimics the action of an endogenous satiation signal
and consequently reduces caloric intake, the established association between the signal and
ultimate caloric gain is weakened. When repeated over many meals, the individual may
simply learn to ignore the elevated signal, at least with regard to changing its behavior. For
example, when food is constant from meal to meal, mouth cues become excellent correlates
of caloric intake. If the customary food is diluted with nonnutritive filler, animals stop eating
after the customary volume of food has passed through the mouth the first time this occurs,
thereby failing to acquire the habitual calories. Over the course of a few meals, however,
they abandon mouth cues and stomach volume and shift to more proximal signals,
consuming enough bulk to get the customary calories (Adolph, 1947). Likewise, sham-
eating, in which ingested food exits the body at the stomach, is associated with consuming

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huge volumes of food; but it takes several days of experience with the sham-feeding
paradigm before animals completely abandon mouth cues (Davis and Smith, 1990).
There is an important consideration when evaluating pharmacological agents that act on

receptors thought to be important in mediating satiation. Compounds such as CCK have
numerous actions throughout the body. Because some of these actions are important in
influencing digestion and other processes related to energy homeostasis, changes in the
secretion and consequent levels of these compounds have historically been temporally
associated with meals, and because the nervous system has receptors to detect the levels of
these compounds, the compounds can acquire the ability to act as conditioned stimuli and
influence eating behavior when conditions are stable and predictable. Once those criteria are
no longer met, however, the ability of the compounds to influence behavior is lost (Duncan
et al., 2005; Goodison and Siegel, 1995), although their ability to alter nonbehavioral
metabolic processes presumably remains.
Interactions of Satiation Factors

Key questions relate to which signals take precedence when several are present
simultaneously, how they interact, and whether some signals are hard-wired to drive
consumption in one direction or the other. (Note that in most molecular biology/genetic
experiments, environment is held constant, and there is an implicit assumption that what is
being investigated is hard-wired.) Another consideration is whether repeatedly administering

a compound that elicits premature satiation or that constantly implies elevated body
adiposity will cause the compound to become ignored over time, limiting therapeutic
potential. Normally the messages related to available nutrients in the blood, to a meal being
consumed, and to adipose stores are congruent and the issue is moot, but this need not
always hold. For example, what occurs when distal and proximal cues give mixed
messages? One obvious possibility is that the more proximal cues should predominate, since
they are more closely tied to caloric content. Although few experiments have directly
assessed this, intermediate signals do trump distal signals such as taste and other oral
factors, for when exogenous CCK is administered to bolster the total CCK signal, animals
and people ignore what has passed through the mouth and eat less food. Studies in which
nutrients are reduced locally in the hypothalamus at the same time that peripheral satiation
signals are increased would be informative on these points.
Proximal Signals
Proximal signals that influence satiation as well as other metabolically relevant processes
reflect actual usable energy and include energy-rich molecules (e.g., glucose, fatty acids)
that interact with receptors on specialized cells and/or their ability to alter activity of
intracellular enzymatic cascades or their metabolites. Receptor cells for proximal satiation
signals are located in several regions of the hypothalamus, brainstem, and elsewhere. The
enzymatic cascades in these cells that are influenced by nutrients are the subject of intense
scientific inquiry in the search for novel therapeutic agents to treat obesity (Kahn and Myers,
2006; Woods et al., 2008). The hypothalamic arcuate nucleus (ARC) is an important site
where proximal satiation signals interact with adiposity and other signals, and although the
ARC serves as a convenient example in the following discussion, this is not intended to
minimize the importance of other brain areas important in energy homeostasis.
The major output of the ARC is a pair of parallel neuronal circuits with functionally
opposite actions, one providing an anabolic tone and the other providing a catabolic tone
(Seeley and York, 2005). The balance between these two output systems is a major
determinant as to whether more food is ingested and more fat laid down (i.e., anabolic
activities) or else eating is suppressed and the body relies on stored fat for energy (i.e.,

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catabolic activities). ARC catabolic neurons synthesize pro-opiomelanocortin (POMC),

which is processed into α-melanocyte-stimulating hormone (αMSH). αMSH in turn acts at
melanocortin (MC) receptors (especially MC4 receptors) in several brain areas to reduce
food intake. MC4 agonists elicit hypophagia and weight loss, whereas MC4 antagonists
cause hyperphagia and weight gain, and chronic reduction of αMSH activity results in
extreme obesity (Naslund and Hellstrom, 2007). ARC anabolic neurons synthesize
neuropeptide Y (NPY) and agouti-related protein (AgRP). Although NPY has diverse
actions throughout the brain, ARC NPY acts on Y receptors to increase food intake, and if
NPY is administered chronically, animals gain body weight (Beck, 2006). AgRP is an
antagonist at MC4 receptors, and administration of AgRP or synthetic MC4 antagonists
increases food intake and body weight (Flier, 2006).
Both the anabolic and the catabolic ARC circuits are normally active, such that manipulation
of either the αMSH catabolic system or the NPY/AgRP anabolic system, in either direction,
shifts the balance of control (Schwartz et al., 2000; Seeley and York, 2005). It is as if the
ARC is simultaneously applying an accelerator and a brake to circuits controlling energy
homeostasis, and that adjustments can be made to strengthen or lessen either side of the
equation in the service of homeostasis. Both POMC and NPY/AgRP cells express both
leptin and insulin receptors, and increased levels of either insulin or leptin locally in the
ARC increase catabolic and decrease anabolic activity; the ability of leptin or insulin to
reduce food intake is attenuated when the melanocortin system is blocked (Benoit et al.,
2002; Seeley et al., 1997). Analogously, decreased leptin or insulin activity within the ARC
increases food intake and weight gain (Munzberg and Myers, 2005; Obici et al., 2002).
Key for consideration of satiation, certain cells, including some ARC neurons, respond to
changes in the activity of their own intracellular metabolic processes by generating
messages that are passed to other cells and that influence the control of food intake and
plasma glucose (Levin et al., 2004). For example, glucose-excited neurons in the ARC
synthesize POMC and secrete αMSH (Ibrahim et al., 2003), whereas glucose-inhibited
neurons secrete NPY (Muroya et al., 1999), and changes of glucose in the ARC elicit neural
reflexes to the liver and the endocrine pancreas to modify plasma glucose. Local increases of
oleic acid and some long-chain acetyl-CoAs (Lam et al., 2005) or the branched-chain amino
acid leucine (Cota et al., 2006b) also initiate signals in ARC neurons. Hence, ARC neurons
have several properties pertinent to the control of food intake. They directly sense and
respond to local levels of energy-rich nutrients, they have receptors for adiposity signals,
they receive information concerning satiation that is relayed from the hindbrain, and they are
the origin of two major pathways influencing homeostatic balance. Thus, any of several
possible inputs to the ARC can reduce feeding, including increased nutrients, increased
satiation signals, or increased adiposity signals. These same signals also act in the ARC to
influence glucose homeostasis.
In sum, numerous signals related to food intake converge on the hypothalamus, including
the ARC. These hypothalamic areas comprise an important site of interaction of satiation
and adiposity signals, and they modulate distinct anabolic and catabolic circuits to hindbrain
areas directing meal size and plasma glucose. Administration of either insulin or leptin into
the ARC area reduces food intake and body weight, and this is manifest as reduced meal
size. Consistent with this, both insulin and leptin increase sensitivity to satiation factors such
as CCK (Matson et al., 2000; Riedy et al., 1995).
Analogous to what occurs at the level of the whole animal, individual ARC neurons respond
both to energy-rich proximal signals as well as to an array of distal cues. At the cellular
level, distal cues are hormones and neurotransmitters generated in other, often remote, cells
or tissues. Insulin is a distal cue, reaching receptors on ARC neurons in proportion to

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glucose reaching the pancreas in the recent past, and the ARC leptin signal reflects stored
fat. One consequence of a change of ARC insulin or leptin signaling is altered food intake.
The lag between changes of secretion and altered insulin or leptin signaling in the brain
ranges from seconds to minutes or more. Neurotransmitters are distal signals but with a
relatively short time constant. The target cell in turn integrates all of these signals and
appropriately adjusts its neuronal output as well as its own energy intake, storage, and
utilization. In a stable environment, the integrated message to ARC neurons is coordinated
and consistent. Increased glucose interacting with receptors on the tongue, intestine, or liver
elicits neuronal signals that arrive in the ARC prior to the local influx of new glucose
molecules. ARC neurons are thus primed to be responsive to subsequent signals indicating
increased available energy (i.e., via signaling from insulin, CCK, or increased local
glucose).
Because energy-sensing cells in the ARC (and elsewhere) convert activity in fuel-sensitive
enzymatic cascades into a signal that can be transmitted to other cells, intense research effort
is aimed at determining precise receptor activity and/or intracellular enzyme activity that
influence the output of cells to identify potential therapeutic targets. Hypothetically, the
input to and hence output of these cells could be manipulated to provide a false message to
brain areas controlling food intake and metabolism; i.e., if pivotal signaling cells could be
pharmacologically tricked into responding as if there were more fat in the body than actually
exists, or more glucose in the blood, reflexes could be activated to reduce food intake or
glucose secretion from the liver.
Like most cells in the body (Woods et al., 2008), ARC energy-sensing neurons have dual
intracellular kinase cascades that control their own metabolism, one activated when
available energy is low (AMP-activated protein kinase, AMPK) and one when available
energy is high (mammalian target of rapamycin, mTOR). Because increased AMPK activity
elicits a coordinated pattern of cellular processes to reduce nonessential activities and
acquire new energy (Hardie, 2007), AMPK is a proximal signal for insufficient energy.
Conversely, mTOR is a proximal signal of increased intracellular energy. Neuronal AMPK
is elevated by low glucose and by distal cues, such as AgRP or ghrelin, signifying nutrient
need (Minokoshi et al., 2004). These distal signals increase during fasting and decrease upon
refeeding, and they stimulate AMPK in ARC neurons. Consistent with this, administration
of AgRP or ghrelin locally in the hypothalamus increases food intake. Conversely, leptin
and insulin reduce ARC AMPK activity. Increasing AMPK activity in the ARC increases
food intake and attenuates leptin anorexia (Minokoshi et al., 2004).
In contrast, ample intracellular energy increases mTOR activity, and the converse is true
when energy is low. Like AMPK, mTOR activity is also sensitive to distal cues.
Phosphorylation of some downstream products of mTOR occurs only in ARC NPY/AgRP

and POMC neurons (Cota et al., 2006a). Thus, mTOR activity in ARC nutrient-sensing
neurons varies with feeding status. Fasting decreases ARC mTOR, and refeeding increases
it. Increased leptin locally near the ARC phosphorylates the mTOR enzymatic cascade, and
the ability of leptin to reduce food intake is attenuated by mTOR inhibitors (Cota et al.,
2006a). Thus, the reciprocal activities of ARC AMPK and mTOR are positioned to integrate
adiposity signals with local energy availability, including glucose and some fatty acids and
amino acids.
Implications
Eating, including both the initiation and termination of meals, is a complex behavior that
interacts with the reflexive control of plasma glucose, with the maintenance of body fat, and
with many other regulated parameters. Eating itself is not a regulated variable, but rather

Woods Page 10
functions in the service of other parameters. To take body fat as an example, individuals
readily abandon a preferred eating pattern when constraints are imposed; i.e., they eat at
different times, or more often, or adopt whatever strategy allows them to acquire sufficient
calories to maintain body fat (Collier and Johnson, 2004; Woods, 2002).
A broad array of signals influences both the onset and offset of eating, focusing attention on
already-present inputs. An important principle is that it is advantageous to accurately know
when to start eating and when to stop eating, and the sooner these behaviors can be
pinpointed, the better the individual can prepare for the meal’s consequences (Woods,
1991). Hence, signals that herald a meal is imminent elicit cephalic responses, such as
increased insulin and ghrelin, prior to the start of the meal (Drazen et al., 2006; Teff, 2000).
Time of day is often a key determinant of meal time, and animals can also learn to make
meal-anticipatory behaviors in response to arbitrary stimuli that reliably indicate food
availability, and those same stimuli can elicit eating, even in sated animals (Sclafani, 1997).
The point is that the most reliable indicators of food availability acquire the ability to control
meal onset.
With regard to meal size, in most laboratory experiments, signals ranging from taste and
smell to mouthfeel, to gastric distension, to CCK, and other gastrointestinal secretions are
highly and equally correlated with ingested calories. Hence, the experimental manipulation
of any of these signals elicits acute changes of meal size, but at the cost of dissociating the
signal from its established link with subsequent metabolic changes. If such trials are
interspersed only occasionally, the intervening normal meals serve to restore the signal’s
potency. However, if a signal is repeatedly and reliably dissociated from metabolic
consequences, animals learn to ignore it, focusing on other more reliable correlates of
ingested calories. This is problematic for therapeutic strategies aimed at controlling food
intake by mimicking one or another naturalistic satiation signal.
A number of questions follow from this analysis: which signals are hard-wired genetically
and/or modifiable by experience? Can any signal, internal or external, be co-opted to
influence food intake chronically? Can an animal learn to disregard one or another signal
within the ARC: e.g., of glucose, insulin, or AMPK? The answers to such questions would
go a long way toward identifying which factors take precedence in the energy homeostatic
calculus and would also shed light on which type of signal should be developed if
controlling eating is a therapeutic endpoint.
The model presented here has implications for obesity. For example, some believe that the
increased burden of everyday stressors is a culprit in stimulating food intake and consequent
weight gain (Adam and Epel, 2007). The concept of comfort foods is a case in point
(Dallman et al., 2005). When consumed, comfort foods reduce the stress response such that
some individuals, faced with unavoidable stressors, self-medicate by ingesting these foods.
Comfort foods are often calorically dense and palatable such that their frequent consumption
predisposes to obesity. It is worth pondering why comfort food is comforting; i.e., is it
because there is a genetic basis for some foodstuffs to activate systems that create pleasant
sensations and/or suppress stress? Or is it that individuals have learned what to expect when
they eat these foods and that there is comfort in knowing how the metabolic sequellae will
play out when they are eaten? It may be that “comfort” is a consequence of being able to
rely on distal cues when eating; i.e., in a changing, stressful world, there is an advantage to
knowing that nutrients will be handled appropriately in advance of the actual entry of
nutrients into the blood, so that effort can be diverted elsewhere to confront life’s other
stressors (Ulrich-Lai et al., 2007). The point is that knowing when and how much will be
eaten and the metabolic consequences of the act bestows an advantage for coping with life

Woods Page 11
events. Opting for foods or food-related cues with a high degree of predictability may be a
logical and economically viable response; it eliminates metabolic surprises.
There are several perspectives from which to consider the act of eating. It can be
opportunistic, taking advantage of windfalls and other unpredictable situations. More often
eating is habitual, the precise timing and specific eating situations being idiosyncratic and
predictable, depending upon an individual’s unique history. A key point is that food intake
itself is not a regulated variable but rather assists in the homeostatic maintenance of other
variables that are themselves regulated, including body fat and blood glucose. As a result,
when the environment allows, individuals have the luxury of adopting regular eating
patterns that reflect a balance among many factors, including food availability, the social
situation, and others. However, if constraints are superimposed on meal taking, animals
abandon their preferred eating pattern in order to protect critical regulated parameters. For
example, rats with food freely available prefer to spread their intake out, consuming
numerous relatively small meals each day (Collier and Johnson, 2004). When required to
exert considerable effort to gain access to their food, but able to eat as much as desired once
food is available, they change their strategy, consuming a few large meals each day such that
total daily intake and body weight remain constant. Likewise, if limits are placed on meal
size, animals respond by eating more meals each day, again defending body weight (West et
al., 1984).
If blood glucose (or glucose utilization) is acutely and severely reduced, eating is elicited
(Langhans, 1996). This is generally considered an emergency response, since normal meals
occur at glucose levels considerably above those extremes. Nonetheless, if glucopenic eating
is repeated on a chronic basis, the enhanced daily caloric intake is sufficient to cause weight
gain (Langhans, 1996). Thus, although the maintenance of body weight and blood glucose
both interface with eating behavior, protecting blood glucose takes priority over maintaining
a desired body weight when the two are pitted against each other. The point is that the size
and pattern of meals are flexible and often represent compromises among the regulation of
several variables.
Thus, if designing pharmacotherapies to treat obesity is a goal, targeting meal size is not an
optimal strategy, as other factors can intervene and interfere with the ultimate goal. A better
strategy is to take advantage of the fact that food intake is reflexively reduced when the
brain senses that the body is excessively fat. Signals such as insulin and leptin stimulate the
brain in proportion to body fat, an increased signal activating catabolic circuits and a
decreased signal activating anabolic circuits (Schwartz et al., 2000; Woods et al., 1998).
This negative feedback aspect of body fat regulation is considered a major factor in the
stability of weight over time and for the inevitable regain of body weight lost after dieting.
The same process could presumably be harnessed to reduce body weight in obese
individuals.
What is key regarding the weight-regulatory system is that its impact does not appear to
dissipate over time; i.e., animals with a reduced leptin or insulin signal locally in the brain
maintain a chronically elevated body weight, and elevating insulin or leptin locally in the
brain causes weight loss as long as the treatment is maintained. What is pertinent is that food
intake can be co-opted to achieve and maintain a particular level of weight. For example,
animals typically eat less food when the insulin signal is increased in the brain (Schwartz et
al., 2000; Woods et al., 1979, 1998). However, this does not mean that insulin causes an
obligatory decrease of food intake in the brain. For whereas normal-weight controls eat less
and lose weight when administered insulin into the brain, rats that have already lost
significant weight actually increase their food intake when administered insulin into the
brain, bringing their weight to the same level achieved by the controls receiving insulin

Woods Page 12
(Chavez et al., 1995). The point is that the insulin seen by the brain dictated a certain level
of body weight to be achieved, and changes of food intake, whether decreases or increases,
were used to attain that weight.
The implication is that therapeutic strategies that mimic the action of adiposity signals in the
brain are much more likely to accomplish desired endpoints than strategies targeting food
intake per se. As discussed above, the factors that control individual meals are malleable,
and meal patterns themselves are readily changed. Providing a signal to the brain that excess
fat exists in the body allows homeostatic controls to rein in food intake in an optimal way.
Conclusions
In order to meet the continuous demand for energy, organisms utilize diverse signals at both
the organismic and the cellular levels to optimize energy homeostasis. The coordinated
regulation of these processes relies upon opposing effector systems at every level. Nutrient-
sensing neurons in the ARC and elsewhere integrate distal and proximal signals to control
their own metabolism as well as to generate signals transmitted to other cells, thereby
changing the balance of anabolic and catabolic circuits directing behavioral, endocrine, and
autonomic responses. The dual neuronal-circuitry response is mirrored by opposing intra-
cellular enzymatic cascades (AMPK and mTOR), whose activity in turn affects food intake
and body weight. An important point is that other factors, such as exposure to a high-fat diet,
influence the sensitivity of these hypothalamic systems to hormonal and nutrient signals,
predisposing to weight gain and/or dysregulated glucose. Considering the urgency that our
society faces in curtailing the epidemics of obesity and type 2 diabetes, intense research is
needed to understand how dietary constituents and energy content influence hypothalamic
sensitivity to homeostatic signals.
Few behaviors of advanced organisms are simple knee-jerk reactions to sudden inputs or
changes. Regulatory behaviors in particular must be plastic and adaptable in order to provide
maximum flexibility for coping with a variable world. Eating is a behavior that serves many
masters, including maintaining long-term energy stores with the least perturbation to
circulating glucose and other fuels. Eating must be sufficiently opportunistic to take
advantage of environmental windfalls and at the same time be integrated and coordinated
with the myriad other behaviors in the individual’s repertoire. It would be maladaptive to
constrain such an enterprise by making it a slave to specific stimuli relevant to one or
another aspect of metabolism, and there is compelling evidence that this is not in fact how it
works. Rather than being tied to specific stimuli, both the onset and termination of meals are
able to exploit whichever signals guarantee the best outcomes, and these vary with past
reliability and experience. Because of this, uninformed pharmacological approaches to
control eating chronically may prove fruitless, as the chronically treated individual could
easily switch to more reliable cues; i.e., a deeper understanding of the system will be
necessary to provide insights as to how the system can be exploited to achieve metabolic if
not behavioral endpoints.
Acknowledgments
Consideration of these topics benefited from discussion with many individuals, including Randy Seeley, Douglas
Ramsay, Randall Sakai, Debbie Clegg, Stephen Benoit, Dan Porte, Michael Schwartz, Wolfgang Langhans, Nori
Geary, Thomas Lutz, Gertjan van Dijk, Anton Scheurink, Mary Dallman, Elissa Epel, Daniela Cota, Matthias
Tschöp, Silvana Obici, David D’Alessio, Patrick Tso, James Herman, Yve Ulrich-Lai, and Ed Stricker. This work
was supported in part by DK 067550 and DK 017844.

Woods Page 13
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Woods Page 17
Figure 1. Physiology of Satiation

Several categories of signals converge on the brain to influence energy homeostasis.
Satiation signals such as CCK and GLP-1 arise from the gastrointestinal tract and related
organs during meals and are conveyed to the hindbrain. Adiposity signals are hormones
whose secretion is proportional to body fat and that stimulate receptors in several areas of
the brain, including the hypothalamic arcuate nucleus (ARC). Energy-rich nutrients also
provide a direct signal to the ARC. These sensory inputs are integrated with circuits from
other brain areas related to cognitive, social, and emotional activities, and the output alters
food intake, energy expenditure, and ultimately body adiposity.

Woods Page 18
Figure 2. Satiation Signals

Satiation signals can be partitioned in terms of their relationship to the caloric content of
food being eaten. Distal signals such as the taste and smell of food occur relatively early
during meals and have a low and variable degree of reliability to caloric content.
Intermediate signals such as CCK and GLP-1 are secreted in response to the
physicochemical properties of ingested food as it interacts with receptors in the
gastrointestinal lumen. Proximal signals are energy-rich nutrients themselves and/or the
consequences of their local metabolism in the brain, and they arise later in time than distal or
intermediate signals.

Woods Page 19
Figure 3. Modeling the Satiating Effect of an Exogenous Compound

Satiation is hypothesized to occur and the ongoing meal therefore hypothesized to end when
a satiation threshold is reached. Early in a normal (control) meal (Time A), when not many
calories have been consumed, mouth factors (MF) and gastric distension (GD) presumably
combine with intermediate signals such as amylin (AMY), glucagon (GL), and CCK,
providing an integrated satiation signal insufficient to cause the meal to end. Later during
the meal (Time B), other signals such as GLP-1 (GLP) and PYY come online, increasing the
total satiation signal. If an exogenous satiation factor such as CCK has been administered
(test meal), the combined satiation signal (endogenous plus exogenous factors) is sufficient
to reach threshold, and eating stops. Normally, however, more food is consumed (Time C),
and other factors such as perhaps nutrients themselves (NUT) enter into the calculus, and the
meal ends when the combined endogenous signals reach threshold.

The Control of Food Intake: Behavioral vs Molecular Perspectives

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Cell Metab. 2009 June ; 9(6): 489–498. doi:10.1016/j.cmet.2009.04.007.

The Control of Food Intake: Behavioral versus Molecular

pharmacological targets to control body weight.

Exogenous administration of compounds that stimulate the receptors for endogenous

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Factors that Influence Meal Size

Cell Metab. Author manuscript; available in PMC 2011 May 10.

making meal-anticipatory responses, the change can as easily be attributed to knowing a

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Control of Meal Onset and Meal Size

An important goal of experiments evaluating factors that influence food intake is to

Cell Metab. Author manuscript; available in PMC 2011 May 10.

There is an important consideration when evaluating pharmacological agents that act on

Interactions of Satiation Factors

being investigated is hard-wired.) Another consideration is whether repeatedly administering

Cell Metab. Author manuscript; available in PMC 2011 May 10.

catabolic activities). ARC catabolic neurons synthesize pro-opiomelanocortin (POMC),

influence glucose homeostasis.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

glucose secretion from the liver.

Phosphorylation of some downstream products of mTOR occurs only in ARC NPY/AgRP

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Neurosci. 2005; 8:566–570. [PubMed: 15856064]

Cell Metab. Author manuscript; available in PMC 2011 May 10.

free-feeding rats. Am J Physiol. 1984; 246:R776–R787. [PubMed: 6326618]

Cell Metab. Author manuscript; available in PMC 2011 May 10.

involving mTOR. Annu Rev Nutr. 2008; 28:295–311. [PubMed: 18429698]

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Figure 1. Physiology of Satiation

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Figure 2. Satiation Signals

Cell Metab. Author manuscript; available in PMC 2011 May 10.

Figure 3. Modeling the Satiating Effect of an Exogenous Compound

Cell Metab. Author manuscript; available in PMC 2011 May 10.

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