Appetite control and energy balance regulation in the modern world: Reward-driven brain overrides repletion signals

Abstract

Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have been identified as the strongest signals to induce adaptive biological actions such as increased energy intake and reduced energy expenditure. In concert with other signals from the gut and metabolically active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems involved in finding potential food sources, smelling and tasting food, and learning to maximize rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus lead to a 'hungry' brain, preoccupied with food. By contrast, because of less (adaptive thrifty fuel efficiency) or lost (lack of predators) evolutionary pressure, the upper limits of body weight/adiposity are not as strongly defended by high levels of leptin and other signals. The modern environment is characterized by the increased availability of large amounts of energy-dense foods and increased presence of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle. Much of these environmental influences affect cortico-limbic brain areas concerned with learning and memory, reward, mood and emotion. Common obesity results when individual predisposition to deal with a restrictive environment, as engraved by genetics, epigenetics and/or early life experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone individuals should be seen as a normal physiological response to a changed environment, not in the pathology of the regulatory system. The first line of defense should ideally lie in modifications to the environment and lifestyle. However, as such modifications will be slow and incomplete, it is equally important to gain better insight into how the brain deals with environmental stimuli and to develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease. It will be crucial to understand the functional crosstalk between neural systems responding to metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic circuitry.

Full text

Appetite control and energy balance regulation in the modern
world: Reward-driven brain overrides repletion signals
Huiyuan Zheng, Natalie Lenard, Andrew Shin, and Hans-Rudolf Berthoud
Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center Louisiana State
University System, Baton Rouge, Louisiana, USA
Abstract
Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of
body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have
been identified as the strongest signals to induce adaptive biological actions such as increased energy
intake and reduced energy expenditure. In concert with other signals from the gut and metabolically
active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems
to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems
involved in finding potential food sources, smelling and tasting food, and learning to maximize
rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus
lead to a “hungry” brain, preoccupied with food. In contrast, because of less (adaptive thrifty fuel
efficiency) or lost (lack of predators) evolutionary pressure, upper limits of body weight/adiposity
are not as strongly defended by high levels of leptin and other signals. The modern environment is
characterized by increased availability of large amounts of energy dense foods and increased presence
of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle.
Much of these environmental influences impact cortico-limbic brain areas concerned with learning
and memory, reward, mood, and emotion. Common obesity results when individual predisposition
to deal with a restrictive environment as engraved by genetics, epigenetics, and/or early life
experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone
individuals should be seen as a normal physiological response to a changed environment, not in
pathology of the regulatory system. The first line of defense should ideally lie in modifications to
the environment and lifestyle. However, because such modifications will be slow and incomplete, it
is equally important to gain better insight how the brain deals with environmental stimuli and to
develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such
as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease.
It will be crucial to understand the functional crosstalk between neural systems responding to
metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic
circuitry.
Keywords
Neural control of appetite; metabolic need; internal depletion signals; environmental food cues;
cortico-limbic systems; food reward; leptin; obesity
Corresponding author: Hans-Rudolf Berthoud Pennington Biomedical Research Center Neurobiology of Nutrition Laboratory 6400
Perkins Road Baton Rouge, LA 70808 Ph: 225-763-2688 Fax: 225-763-0260 berthohr@pbrc.edu.
NIH Public Access
Author Manuscript
Int J Obes (Lond). Author manuscript; available in PMC 2010 March 15.
Published in final edited form as:
Int J Obes (Lond). 2009 June ; 33(Suppl 2): S8–13. doi:10.1038/ijo.2009.65.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Introduction
The obesity epidemic continues unabated with no cure in sight. By increasingly affecting
children and adolescents it is threatening to roll back much of the significant progress made in
developed countries during the last century in living healthy and independent lives and in
creating social harmony and economic productivity. The discovery of leptin over a decade ago
spawned great hope for an end to the obesity crisis, like the discovery of insulin essentially
cured type 1 diabetes half a century ago. That this has not happened, at least not yet, has been
the subject of great debate. How is it possible that the ostensibly perfect negative feedback
signal regulating adiposity permits accumulation of excessive body fat in the first place and
why does leptin treatment not reverse obesity?
In this brief review, we will argue that the inherent asymmetry in the adaptive response to
famine and feast may be responsible for the fact that simply changing the food environment
can push adiposity of a population upwards and result in increased prevalence of obesity. We
will review the emerging literature showing that low leptin together with other hormones and
metabolites signaling relative decreases in nutrient supply powerfully invoke neural
mechanisms of reward, motivation, and decision-making, and how this is exploited by the
modern environment and lifestyle. We will argue that homeostatic defense of the upper limits
of adiposity are inherently weakened by genetic predisposition and/or rapid and reversible
development of resistance to metabolic feedback signals such as leptin. Finally, we will outline
the distributed neural systems involved in appetite control and energy balance regulation and
highlight the importance of crosstalk between the systems traditionally linked to metabolic
regulation and processing of cognition, reward, and emotions.
Strong defense of adequate nutrition and the lower limits of adiposity
Procurement and availability of sufficient energy and essential nutrients is defended by a
complex system consisting of fail-save, redundant pathways (1,2). Larger animals, including
humans, can endure considerable periods without food by burning fat stored in significant
depots and reducing energy expenditure. Smaller animals often do not have significant fat
stores and fall into torpor for survival. In either case, hunger is strongly expressed at least
initially. To organize these life-saving responses we rely on accurate sensors of the internal
milieu and the external world, flexible and adaptive integrators that make sense out of all this
diverse input, and powerful effectors that act both on the input and output arms of energy
balance. The coordinator of this concerted effort to prevent nutrient depletion and restore
energy supply is the brain. Food restriction and fat depletion lead to a “hungry” brain,
preoccupied with food.
Research efforts in the post-leptin discovery era have mainly focused on the “metabolic brain”,
identifying some of the crucial neural circuits in hypothalamus and hindbrain. Clearly, the
hypothalamic neurocircuitry is crucial for body energy homeostasis as indicated by the
development of obesity or leanness after loss or gain of function manipulations of its main
components [e.g. (3)]. It is now thought that the mediobasal hypothalamus is the main hub for
sensing availability of nutrients and for generating an integrated adaptive response to deviations
from adiposity levels that are appropriate for a set of given internal and external conditions
(4,5). Although this circuit is assumed by many to regulate body weight and adiposity within
a narrow set point, much like a thermostat controls room temperature, this view has been largely
abandoned in favor of a more flexible regulator that can learn from past experience and adapt
to changing environmental factors (floating set point). Arguably, the major force “designing”
the system was the constant struggle throughout evolution to find enough food for survival,
resulting in a very strong defense of the lower limits of adiposity.
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However, to understand how metabolic need is translated into strong behavioral actions that
successfully compete with other motivated behavior, the role of the “cognitive and emotional
brain” can no longer be neglected.
Cortico-limbic pathways coordinate metabolic need with the external world
It is clear that the neurocircuitry originating from the primary energy sensors in the arcuate
nucleus described above is embedded in a much larger neural system that allows adaptation
and coordination of metabolic needs to the demands and intricacies of the prevailing
environment. For example, it does not make sense for the hungry vole to leave the burrow if
the weasel waits outside. In fact, much of the brain has evolved to take care of hunger ever
since mobile life forms emerged. Although procuring food in our modern environment is no
longer difficult or potentially hazardous, it used to be a demanding task for most of the last 5
million years. Even more primitive invertebrate animals such as honey bees and ants use
elaborate navigation and communication strategies to secure food sources and guarantee
survival for the individual as well as society (6-8).
We remember past experiences with foods, particularly if the experience was out of the
ordinary. A growing number of studies suggest that representations of experience with foods
are generated in the orbitofrontal cortex, an area in the prefrontal cortex that receives
converging information through all sensory modalities (9). Therefore, representations contain
a number of sensory attributes, including shape, color, taste, and flavor, as well as links to time,
location, social context, cost, and reward expectation (9,10). The orbitofrontal cortex is in
intimate contact with other cortical areas, particularly the anterior cingulate, perirhinal and
entorhinal cortices, as well as with the hippocampal formation and the amygdala, often
collectively referred to as paralimbic cortex [for review see (9)]. It is within these areas that
polymodal representations are thought to be available as working memory for constant
updating.
A strong basic drive or motivation was necessary to leave the safety of a burrow or cave and
procure nutrients in a dangerous environment with predators and toxic plants. Emotions
evolved as a mechanism to reinforce beneficial and suppress potentially harmful stimuli and
behaviors. For example, the sweet taste of certain foods and the process of satiation are
associated with positive emotions that augment the motivational drive to find food and eat.
Similar to sexual pleasure, the feelings of satisfaction and well being generated by eating result
in strong motivation to engage in these behaviors again. The reward value of a particular food
is bundled with the other attributes into the stored representations discussed above. Thus, life
is all about learning how specific behavioral responses or actions lead to positive emotions or
reward in the future.
An expanded view of energy homeostasis
It was originally thought that the classic nutritional feedback signals such as leptin, insulin,
gut hormones, and circulating nutrients themselves, act mainly on a few areas of the brain such
as specific parts of the hypothalamus and brainstem. However, recent studies suggest that these
metabolic signals have a much broader influence on brain functions.
For example, leptin has been shown to modulate food-related sensory input signals of all
modalities even at early stages of processing, so that low leptin levels can dramatically lower
detection thresholds of external stimuli signaling availability of nutrients (11-14). Leptin and
insulin can also act directly on mesolimbic dopamine neurons to modulate ‘wanting’ of food
(15-17). Neural activity in the nucleus accumbens elicited by visual food stimuli is very high
in genetically leptin-deficient adolescents and promptly returns to normal levels upon leptin
administration. While in the leptin deficient state, nucleus accumbens activation was positively
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correlated with ratings of liking in both the fasted and fed state, it was correlated only in the
fasted state after leptin treatment and in normal individuals (18). The lower gut hormone PYY
(3-36), which has now been convincingly demonstrated to suppress food intake in humans and
rodents(19), also modulates activity of the ventral tegmental area (VTA) and ventral striatum
(20). In contrast to leptin, the gut hormone ghrelin appears to facilitate foraging behavior and
increase reward processing as part of its orexigenic action (21-25).
Dieting in overweight or obese humans has a very high failure rate, with most of them
developing strong food cravings and inevitable relapse. The mechanisms of this paradoxical
behavior have not been clear. The homeostatic regulatory system could be expected to
cooperate in voluntary weight loss not make it difficult. However, comparing brain activity
changes elicited by visual food stimuli in obese subjects before and after losing 10% body
weight through dieting revealed the anatomy of a “hungry” brain. It is important to note that
after a 10% weight loss these individuals were still obese with lots of excess adipose tissue.
Still, looking at pictures of food evoked much larger changes in brain activity after this
moderate weight loss. Although activity changes were found in the traditional homeostatic
areas of hypothalamus and brainstem, many cortico-limbic areas involved in cognitive and
emotional functions were most strongly affected by the weight loss (26). Importantly, most of
these changes were fully reversed after leptin administration, and leptin treatment during
dieting increased the chance to reach the weight loss goal and prevent relapse in another cohort
of obese patients (27).
Thus, the traditional view of neural circuits regulating energy homeostasis has been expanded
to include neural mechanisms of learning and memory, reward, attention, decision-making,
mood, and emotionality. Adequate supply of energy is simply too important as not to include
these powerful neural processes. To distinguish eating driven by internal, metabolic hunger
signals from eating driven by hedonic, environmental signals in the absence of metabolic need,
the terms “homeostatic” and “non-homeostatic” controls of appetite have recently been adopted
(28-31). In light of the intimate neural interactions between these two classes of signals, this
distinction may have been premature. Metabolic signals can modulate the cortico-limbic
systems involved in higher brain functions, and the cortico-limbic systems can hijack the
behavioral/metabolic effector mechanisms controlling energy balance. Together they serve one
purpose – to maintain an optimal internal millieu in harmony with the external world.
Why does feedback from nutrient repletion signals not prevent obesity?
Weak defense of the upper limits of body weight
Evolutionary pressure has also existed to defend the upper limits of adiposity and, perhaps
more likely, body weight (32). Disadvantages of elevated body weight are evident in the
relationship between prey and predator – a heavier rodent is more likely to become prey of a
weasel or bird compared to a lean rodent. Humans too were prey of larger predators, but the
selection pressure for leanness disappeared with the use of weapons, fire, and shelter. The loss
of selection pressure allowed the upper boundaries of adiposity and body weight to drift
upwards by random genetic mutations over the last 2 million years or so (32).
Natural resistance to negative feedback signals
We now know that in most humans, obesity is a state of leptin resistance with high circulating
leptin levels, and the finding that very few obese patients respond favorably to exogenous leptin
was a major disappointment (33,34). Animal studies have shown that the same thing happens
to laboratory rats and mice, domesticated animals like cats and dogs, as well as wild animals
like polar bears and baboons, when they are exposed to human-like diets high in fat, sugar, and
energy (35,36). Therefore, in contradiction to all the body weight set point and adipostat
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theories positing leptin as the key negative feedback signal, slowly increasing circulating leptin
levels do not prevent development of obesity in many individuals. Rises in other anorexigenic
hormones such as insulin and amylin, as well as metabolites such as glucose and fatty acids
are also not doing their expected job, and neither do decreases in the orexigenic gut hormone
ghrelin. If prone individuals are exposed to the modern environment, the energy balance system
simply equilibrates at a new higher level of body weight/adiposity, completely disregarding
absolute values of feedback signals. This suggests that there is no predetermined set point for
body weight/adiposity regulation, but that body weight/adiposity is defended within a range
that depends on environmental conditions and individual predisposition.
Dependence of body weight/adiposity on environmental conditions should not be too
surprising, as it makes a lot of sense for an organism to store extra energy for a rainy day. This
is illustrated in seasonal animals, where leptin is ineffective in curbing appetite during summer,
when food is abundant (37). The modern human environment could thus be regarded as the
equivalent of continuous “summer” with natural leptin resistance. Before the modern era, this
“summer” used to be broken by winters and famines that quickly restored leptin sensitivity.
This seems to be confirmed by better success with leptin-treatment when it is given as an
adjunct to moderate food intake restriction (27,38). A state of natural leptin resistance may be
accomplished by increased expression of negative modulators of leptin receptor signaling.
These intracellular signaling molecules could act as rapid molecular switches to turn leptin
sensitivity on and off, depending on a particular combination of internal and external factors.
The modern environment acts on cortico-limbic systems to over-stimulate food intake
The major direct environmental factors thought to contribute to increased energy intake are
availability, portion size, energy density, palatability, variety, and presence of food cues. Other
important factors indirectly leading to poor food choice and overeating can be found in
agricultural policies, pricing strategies, socioeconomic status, level of education, and stress
vulnerability. The potential obesogenic role of many of these factors and recommendations for
dealing with them have been reviewed recently [e.g. (39,40)]and will not be further discussed
here.
While there has been a flood of studies demonstrating the acute food intake stimulatory effects
of such environmental factors [e.g. (41,42)], or correlations of exposure to such factors with
body mass index (43), few controlled interventional studies have demonstrated cumulative
effects on food intake and increases in body weight by selectively changing one of these factors.
In one such controlled clinical study, it was shown that increased portion size leads to
significantly increased energy intake and weight gain over a period of 11 days (44). Many more
such studies will be necessary to determine the relative importance of each factor and the
capacity to interact with other factors in specific populations. However, it is already quite clear
that the modern food environment has changed, and promotes increased energy intake and
sedentary behavior.
The modern environment primarily impinges on higher brain functions such as learning and
memory, reward optimization, attention, planning, and execution, organized mainly in cortico-
limbic circuits. As discussed above, these brain systems are essential for efficient food
procurement and they are specifically targeted by the advertising industry (45-47). As shown
by using subliminal stimuli, such processes of memory formation and recall, reward evaluation,
and preparation for motivated actions often take place outside awareness and thus partially
escape conscious executive control (48,49).
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Conclusions
The relative ineffectiveness of current pharmacological and dietary approaches to prevent or
reverse obesity makes sense when considering the complex and redundant neural systems
conferring the strong basic drive to eat. The lower level of body weight/adiposity is staunchly
defended. Low leptin and other signals resulting from inadequate nutrient reserves turn the
brain rapidly into a “hungry machine”. The slightest relative drop in customary nutrient
availability, even at elevated body weight levels, triggers a powerful response. On the other
hand, the upper level of body weight is only poorly defended, particularly in genetically prone
individuals. This asymmetric response pattern in which the “eat more” command is dominant
over the “stop eating” command inevitably leads to slow and incremental weight gain. Not
unlike the ratcheting action of a car jack, exposure to the environment of plenty pushes body
weight only in one direction - upwards.
Realizing that in this scenario, the primary cause of obesity is seen in changes in environmental
and lifestyle changes, prevention and treatment therapies should first focus on reversing or
modifying some of the most salient changes. Secondly, understanding the neural mechanisms
translating environmental stimuli into behavioral actions will be crucial for the development
of behavioral modification and pharmacological intervention therapies. Finally, development
of pharmacological or surgical tools bolstering existing internal feedback signals or enhancing
their downstream signaling capacity should also be continued.
Acknowledgments
Supported by National Institute of Health DK071082
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Fig. 1.
Schematic diagram showing major factors determining food intake and energy balance in
restrictive and modern environments. The availability of nutrients (internal millieu) is detected
by a plethora of distributed sensors and controls food intake directly through classical
hypothalamic-brainstem pathways and indirectly through modulation of food reward processes
in cortico-limbic structures (blue arrows). Low nutrient availability as, for example, signaled
by low leptin levels, produces very strong sensitization of cognitive and hedonic mechanisms
enabling procurement and ingestion of food as well as generating high reward and satisfaction.
This system evolved in order to guarantee adequate nutrient supply in restrictive environments
requiring a high physical activity level. The modern environment and lifestyle are characterized
by high food availability, abundant food cues, and high food palatability (red arrows), all
enhancing food intake either directly or through the same cortico-limbic systems easily
sensitized by nutrient depletion signals. In addition, the built environment, sedentary lifestyle,
and low procurement costs lead to decreased physical activity and in turn, increased nutrient
availability (green arrows). Obesity develops in prone individuals that either efficiently
translate exaggerated hedonic, cognitive, and/or emotional pressure exerted by the modern
environment and lifestyle into increased eating, or individuals in which energy repletion signals
are not able to suppress hedonic eating, or both.
Zheng et al. Page 9
Int J Obes (Lond). Author manuscript; available in PMC 2010 March 15.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript