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Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Why is obesity such a problem in the 21st century? The intersection

of palatable food, cues and reward pathways, stress, and cognition
Margaret J. Morris a,∗ , Jessica E. Beilharz a , Jayanthi Maniam a ,
Amy C. Reichelt a,b , R. Frederick Westbrook b
a
School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia
b
School of Psychology, UNSW Australia, Sydney, NSW 2052, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Changes in food composition and availability have contributed to the dramatic increase in obesity over
Received 1 July 2014 the past 30–40 years in developed and, increasingly, in developing countries. The brain plays a critical
Received in revised form role in regulating energy balance. Some human studies have demonstrated increased preference for high
15 November 2014
fat and high sugar foods in people reporting greater stress exposure. We have examined neurochemical
Accepted 2 December 2014
changes in the brain in rodent models during the development of obesity, including the impact of obe-
Available online xxx
sity on cognition, reward neurocircuitry and stress responsiveness. Using supermarket foods high in fat
and sugar, we showed that such a diet leads to changes in neurotransmitters involved in the hedonic
Keywords:
Obesity
appraisal of foods, indicative of an addiction-like capacity of foods high in fat and/or sugar. Importantly,
Stress withdrawal of the palatable diet led to a stress-like response. Furthermore, access to this palatable diet
Overeating attenuated the physiological effects of acute stress (restraint), indicating that it could act as a comfort
Hippocampus food. In more chronic studies, the diet also attenuated anxiety-like behavior in rats exposed to stress
Reward (maternal separation) early in life, but these rats may suffer greater metabolic harm than rats exposed
Dopamine to the early life stressor but not provided with the palatable diet.
Memory Impairments in cognitive function have been associated with obesity in both people and rodents.
However, as little as 1 week of exposure to a high fat, high sugar diet selectively impaired place but
not object recognition memory in the rat. Excess sugar alone had similar effects, and both diets were
linked to increased inflammatory markers in the hippocampus, a critical region involved in memory.
Obesity-related inflammatory changes have been found in the human brain. Ongoing work examines
interventions to prevent or reverse diet-induced cognitive impairments. These data have implications
for minimizing harm caused by unhealthy eating.
© 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction – what are the drivers of obesity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2. Effect of obesogenic diets on reward processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Intermittent access models of binge-like behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Incentive learning processes that may underpin overconsumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Cue driven mechanisms of food intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Stress and eating behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Early life stress and other influences on eating behavior/obesity risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Rodent model of early life stress–maternal separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Effects of high energy diets on cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Evidence for effects of high energy diets on human cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Effects of high energy diets on learning and memory in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author. Tel.: +61 2 9385 1560; fax: +61 2 9385 0023.
E-mail address: m.morris@unsw.edu.au (M.J. Morris).

http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
0149-7634/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
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5. Summary and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction – what are the drivers of obesity? than nutrient requirements, and driven by the availability of such
foods (Lutter and Nestler, 2009; Meye and Adan, 2014; Saper et al.,
Obesity is a major health issue in the developed and, increas- 2002). The mesocortical dopamine system plays an important role
ingly, in the developing world; indeed obesity is considered the in reward-related processes. This system extends from the ventral
most serious health issue facing the developed world, formally rec- tegmental area (VTA) via the nucleus accumbens (NAc) to corti-
ognized as such by the World Health Organization (WHO, 2000). cal regions (Di Chiara, 1998), and contains circuits that function to
Obesity is defined based on measurements of body mass index motivate and reinforce food seeking and eating behaviors (Ikemoto
(BMI, overweight ≥25; obese ≥30) (Mei et al., 2002). Clinically, it and Panksepp, 1999). This system also underlies seeking and tak-
is characterized as a condition where excess body fat has accu- ing psychoactive drugs (Ahmed and Koob, 2005; Koob and Le Moal,
mulated to an extent that is detrimental to overall health (James 2005). The fact that such drugs can result in addiction raises the
et al., 2000; Ogden et al., 2007). Current worldwide estimates indi- possibility that highly rewarding, sugar and fat rich foods might
cate that over one billion adults are overweight and that at least also lead to a form of “food addiction”, as binging on such foods,
400 million of these are obese (Finucane et al., 2011). Weight gain like taking psychoactive drugs, evoke a phasic increase in dopamine
is influenced by a range of factors including inherited biological in the NAc shell. This dopamine increase is also observed utilizing
traits, early life experiences, and behavioral, environmental and NAc shell microdialysis in rats binging on sugar solution and high
social factors that influence individual behavior. Work from the fat foods, mimicking the pharmacological effects of many drugs of
Quebec family study has shown that high dietary restraint, high abuse (Avena et al., 2006, 2008; Bocarsly et al., 2014; Rada et al.,
disinhibition and susceptibility to hunger behaviors, in addition 2005).
to short sleep duration, are all associated with excess adiposity
and/or obesity (Chaput et al., 2014). The dramatic increase in obe- 2.1. Intermittent access models of binge-like behavior
sity rates over the past few decades suggest that these changes
are due to environmental, rather than genetic factors (Swinburn Rats provided with intermittent access to sugar, or sugar and
et al., 2004, 2009). Energy intake has increased through the ready fat rich foods for a few hours each day over several weeks exhibit
availability and low cost of energy dense, nutrient-poor foods and behaviors characteristic of addiction. These behaviors include
drinks; especially cereal-based foods (including cakes, biscuits, pies binging, withdrawal, increased motivation or “craving”, and hyper-
and pizza), confectionery and sugar-sweetened drinks (Cook et al., activity similar to that produced by stimulant drugs (Avena et al.,
2001)). These foods contributed almost 36% of adults’ and 41% of 2006; Rada et al., 2005). Consistent with the suggestion that
children’s total energy intake and to 41% and 47% respectively of such foods have addictive-like properties, rats fed palatable high
their total fat intake (Rangan et al., 2008, 2009). While there is fat/high sugar diets have reduced sensitivity to psychostimulant
debate regarding the degree to which sweetened beverage intake rewards, for example, such rats are impaired in acquiring a cocaine-
has contributed to this rise in obesity, the US Department of Agri- reinforced instrumental response (Carroll and Lac, 1998; Wellman
culture reported that per capita soft-drink consumption increased et al., 2007). Moreover, chronic exposure to such foods is associ-
by almost 500% in the past 50 years (Putnam and Allshouse, 1999). ated with long-term alterations in brain reward regions including
Another factor contributing to the rise in obesity is the decrease the striatum (Furlong et al., 2014), again similar to the changes pro-
in energy expenditure through changes in urban design and an duced by chronic exposure to stimulant drugs, such as cocaine and
increased reliance on vehicles and labor-saving devices (Badland amphetamine (LeBlanc et al., 2013; Nelson and Killcross, 2006).
and Schofield, 2006). Obesity is such a health issue because it is an
important determinant of a range of health disorders. Being over- 2.2. Incentive learning processes that may underpin
weight or obese increases the risk of metabolic syndrome, type 2 overconsumption
diabetes, cardiovascular disease, some cancers, respiratory condi-
tions, fatty liver disease, reproductive disorders, depression and Food seeking behaviors are directed to enable the acquisi-
other mental health conditions (Bruce-Keller et al., 2009; Flegal tion of these intrinsically rewarding outcomes. This can lead to
et al., 2007; Haslam and James, 2005). modification of neural processes that underpin appetitive (reward-
This review is based on an invited lecture entitled ‘Why is obe- driven) learning processes – attributing significance to the cues
sity such a problem in the 21st century?’ delivered by Morris to the and responses that predict a significant outcome, termed incen-
International Behavioral Neuroscience Meeting, Las Vegas 2014. tive salience (Robinson and Berridge, 1993). As such, both food and
Covering a range of aspects relevant to our research, it addresses drug associated cues have been shown to increase activity in brain
a number of factors that are associated with obesity and the con- regions involved in learning, memory and motivation including the
sequences of the ready availability of palatable food, including the amygdala, orbitofrontal cortex, and the striatum (Tang et al., 2012).
effects of palatable food on the brain, the role of food cues and the The ‘incentive salience theory’ distinguishes between the hedo-
rewarding aspects of food, in addition to the relationship between nic/pleasure component (‘liking’) of eating and the incentive to eat
stress and food intake. (‘wanting’ or ‘reward-seeking’) when animals are allowed access
to palatable foods. Dysfunction of brain reward systems may lead
2. Effect of obesogenic diets on reward processing to abnormal responsiveness to palatable food and food-associated
cues. Environmental cues or stimuli that occur in conjunction with
Many people report that they feel compelled to eat sweet foods, highly rewarding, palatable foods become imbued with “incentive
even in the absence of metabolic requirements, and animal mod- value”. Over eating as a response to food-associated cues may there-
els have been developed that capture addiction-like aspects of fore reflect a distinction between “wanting” and “liking” (Robinson
palatable high fat/high sugar food consumption that can lead to and Berridge, 1993). “Wanting” is identified with the attribution of
obesity. This consumption is based largely on palatability rather incentive salience to cues associated with palatable food rewards

Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
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and “liking” is the pleasurable effects of the outcome. This model
views obesity as the product of incentive learning processes that
potentiate the effectiveness of food-related cues, promoting eating
behaviors.
Furthermore, changes in opioid receptors that regulate the
hedonic value of palatable foods may disrupt feedback signaling
resulting in enhanced non-homeostatic consumption of palatable
food (Kenny, 2011). This hypothesis is supported by studies in
rodents, including obesity-prone rats, which reveal addiction-like
neuroadaptive responses of the reward circuits following chronic
consumption of obesogenic foods. Johnson and Kenny (2010)
reported that extended exposure to palatable foods led to feeding
behaviors in rats that were resistant to disruption when an aversive
CS predicting electric footshock was presented, and proposed that
such exposure had led to compulsive-like feeding behaviors. The
compulsive nature of this feeding could mean that dietary obese
rats fail to modulate feeding based on negative consequences, or
that the incentive value of the palatable foods was increased to a
point where feeding overpowers aversive events.
In terms of behavioral changes in rodents following palat-
able food exposure, differences have been observed in producing
goal-directed responses for rewarding foods, altered craving-like
behaviors such as enhanced responding for sugar following ces-
sation of the diet (Avena et al., 2005), and changed thresholds
in the self-administration of electrical stimulation of the lateral
hypothalamus (Johnson and Kenny, 2010; la Fleur et al., 2007;
Pickering et al., 2009). Furthermore, studies of withdrawal of palat-
able food access (Martire et al., 2014; South et al., 2012) indicate
that rats restrict their intake of standard laboratory chow following
cessation of palatable high fat/high sugar foods, suggestive of anhe-
donic or withdrawal-like responses. This suggestion is supported
by decreases in mu-opioid and cannabinoid CB1 receptor mRNA,
indicating changes in hedonic processing following cessation of
access to the palatable diet (Martire et al., 2014). Furthermore,
these behavioral changes may also be associated with reduced
dopamine levels and dopamine receptor expression following pro-
longed palatable food intake (Alsio et al., 2010; Di Chiara and Tanda,
1997; Geiger et al., 2009; Johnson and Kenny, 2010; Kenny et al.,
2013; Thanos et al., 2008).
2.3. Cue driven mechanisms of food intake
Unrestrained consumption of palatable food has been shown
to increase the reinforcing and rewarding value of foods, trigger-
ing learned associations between cues that predict the availability
of food rewards. These external, environmental cues, such as the
sight and smell of particular foods, or locations where certain foods
are procured, evoke expectations that a reward will be imminently
received. These cue-specific reactions are proposed to be respon-
sible for continuing drug use in drug-addiction, and in a standard
population, can evoke cravings for particular foods (Jastreboff et al.,
2013; Meule et al., 2012, 2014).
Cue-evoked food seeking behaviors are consistent with the pro-
posal that consumption of palatable foods enhances sensitivity to
cues associated with food reward and increases responsiveness of
reward circuitry to food consumption, potentiating feeding behav-
iors and leading to overconsumption (Volkow et al., 2012). Food
and food-related cues are capable of activating reward associated
brain circuits, and regions including the OFC, insula, amygdala,
hypothalamus, striatum, and midbrain regions including the VTA
and substantia nigra (SN) (Bragulat et al., 2010; Pelchat et al., 2004;
Schur et al., 2009; Simmons et al., 2005). The VTA plays a pivotal
role in cue-induced food seeking, and several neuromodulators
including neuropeptides and hormones involved in hedonic and
homeostatic control of feeding behavior appear to have critical
Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
3
input to reward systems and neurotransmitters, including CB1R,
orexin and ghrelin (Meye and Adan, 2014).
Studies indicate that differences in food reward processing
exist between overweight and lean individuals and in the way
they respond to food associated cues (Burger and Stice, 2011;
Castellanos et al., 2009; Kenny, 2011; Volkow et al., 2012). These
cues can promote food consumption even in the absence of hunger
– so-called cue-induced feeding (Petrovich et al., 2005, 2007, 2012;
Reppucci and Petrovich, 2012; Walker et al., 2012; Weingarten,
1983). In this paradigm, hungry rats or mice are trained to asso-
ciate an auditory cue (CS+) or distinct context with deliveries of
a palatable food. Following training, the animals are permitted to
freely feed on chow in their home cages, so they become sated.
Rats are returned to the training chambers in a sated state and are
presented with the palatable food; greater consumption occurred
when the cue associated with the food (CS+) was presented as
opposed to a cue that was not paired with food (CS−), indicating
that the food-associated cue was capable of evoking a specific moti-
vational state, akin to craving (Petrovich et al., 2005, 2007, 2012;
Reppucci and Petrovich, 2012). Furthermore, following training on
a pavlovian discrimination task where CS1 (e.g., click) predicted
delivery of outcome 1 (cherry sucrose) and CS2 (e.g., tone) predicted
delivery of outcome 2 (grape maltodextrin), we demonstrated that
rats fed a high fat/high sugar cafeteria diet no longer exhibited CS
specific food-seeking responses (magazine entries) in a motivation-
ally appropriate manner following devaluation of one outcome by
sensory specific satiety (Reichelt et al., 2014). This indicates that
access to high fat high/sugar diets impaired control of pavlovian
responding (Reichelt et al., 2014).
It has been proposed that the mesolimbic reward system
increases responsiveness to visual food cues and that the magni-
tude of this neural responsiveness is increased in obesity (Volkow
et al., 2012). However, deficits in reward processing may also
be present in obese individuals in response to overconsumption
of palatable food during the development of obesity. A marked
decline in striatal activity in response to palatable food over this
time period was observed in women who gained weight over a
6-month period (mean BMI increase of 4.1%, range 2.5–8.2%) com-
pared with women who did not gain weight and maintained a
stable BMI, and the increased BMI negatively correlated with stri-
atal activity (Stice et al., 2010). This reduced striatal response to
the consumption of palatable foods may imply a reduction in sen-
sitivity in reward neurocircuitry, leading to overconsumption to
reach a rewarding “threshold”. Recent work links the fat mass
and obesity associated gene (Fto) to the control of dopamine-
2 (D2R) and dopamine-3 receptor (D3R) dependent signaling,
suggesting that humans carrying FTO gene variants may have
alterations in D2R-and D3R-dependent behaviors (Hess et al.,
2013).
A large body of literature indicates that obese individuals can be
hyper-responsive to food cues, demonstrated by increased BOLD
response in reward processing brain regions (Davids et al., 2010;
Demos et al., 2012; Gearhardt et al., 2011; Rothemund et al.,
2007), indicating that obesity changes food-cue reactivity, partic-
ularly in individuals with increased genetic risk of obesity (Karra
et al., 2013; Velders et al., 2012). Furthermore, mesolimbic activ-
ity following the presentation of food cues is positively correlated
with BMI (Grosshans et al., 2012; Loeber et al., 2012). This hyper-
responsiveness to food cues in obese people may be underpinned by
the assignment of an increased incentive value to highly palatable,
energy dense foods, driving overconsumption through augmented
activity within the mesocorticolimbic circuitry (Burger and Stice,
2011; Castellanos et al., 2009; Volkow et al., 2012). Furthermore,
negative affect, such as when under stress, can enhance respon-
siveness to food cues, evoking an attentional bias (Hepworth et al.,
2010). Thus, food-associated cues may promote overconsumption
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in both normal weight and overweight subjects particularly when
experiencing a negative mood.
3. Stress and eating behavior
The neural circuits that regulate energy intake converge on
the paraventricular nucleus, which contains the cell bodies of
corticotrophin releasing hormone (CRH) neurons. The paraventric-
ular nucleus regulates hypothalamo–pituitary–adrenal (HPA) axis
activity and responds to circulating glucocorticoids and insulin
(Dallman et al., 1995; Nieuwenhuizen and Rutters, 2008), thereby
providing overlap between the stress and feeding systems. Glu-
cocorticoids, secreted by the adrenal gland, and insulin from
the pancreas, have opposite effects on feeding responses; the
former increasing and the latter reducing food intake (Strack
et al., 1995). Administration of synthetic glucocorticoid was shown
to promote hyperphagia, body weight gain and hyperinsuline-
mia (Veyrat-Durebex et al., 2012). Glucocorticoids also stimulate
insulin secretion but affect food intake via the orexigenic neuro-
peptide, neuropeptide Y (NPY) (Hanson and Dallman, 1995; Strack
et al., 1995). Glucocorticoids can affect the expression of other
hypothalamic feeding neuropeptides; adrenalectomy decreased
proopiomelanocortin (POMC) and agouti-related peptide (AgRP)
while replacement of glucocorticoids reversed these effects in
rats (Savontaus et al., 2002). A more detailed discussion of the
interactions between glucocorticoids, hypothalamic appetite regu-
latory neuropeptides, and feeding hormones is provided elsewhere
(Maniam and Morris, 2012). Exposure to chronic stress is also asso-
ciated with the development of abdominal obesity in humans.
Bjorntorp (2001) proposed that chronic activation of the HPA
axis by stressors increases glucocorticoid binding to glucocorticoid
receptors (GR). These receptors are highly expressed in abdomi-
nal fat, and in the presence of insulin, stimulation of GR activates
lipoprotein lipase which leads to inhibition of lipid mobilization,
accumulation of triglyceride and retention of abdominal fat. In line
with the link between stress and obesity, those people reporting
a greater number of stressful events had higher BMI (Sinha and
Jastreboff, 2013).
Stress can increase or decrease food intake, in both rodents and
people (Foster et al., 2006; Groesz et al., 2012; Harris et al., 1998;
Marti et al., 1994; McIntosh et al., 1999; Pecoraro et al., 2004; Ryu
et al., 2008; Schulz and Laessle, 2012; Tomiyama et al., 2011). In
rodents, most studies demonstrate that stress reduces food intake,
unless palatable food is present during the stress period; this is
in line with human studies reporting ‘comfort’ eating in response
to stressful situations (Adam and Epel, 2007; Dallman et al., 2006;
Pecoraro et al., 2004; Tomiyama et al., 2011). Such eating is thought
to involve subcortical areas controlling stress arousal and energy
storage (HPA axis and limbic areas) as strong motivational drive
and impulsivity (NAc) (Adam and Epel, 2007). The dopaminergic
system may have a direct influence on the HPA axis. CRH release
following stress has been shown to increase dopamine activity in
the VTA. Wanat et al. (2008) reported that VTA dopamine neuron
firing was dose-dependently increased by CRH, and this firing was
inhibited with CRH-1 receptor antagonism. This effect of CRH on
dopamine suggests that stress evokes a response to avoid the stres-
sor, promoting seeking and eating hedonically pleasant food (Bello
and Hajnal, 2010). The intake of palatable food (lard or sucrose)
was increased during restraint stress exposure and the physi-
ological stress response was reduced, as evidenced by reduced
levels of plasma corticosterone, in rats consuming palatable food
relative to those only consuming chow (Bell et al., 2002; la Fleur
et al., 2005). Similar effects were also reported in human studies
(Macht and Mueller, 2007; Tomiyama et al., 2011). Moreover, the
increased anxiety and hyperactivity of HPA axis induced by early
life stress were reduced in rats provided with a highly palatable
Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
diet (cafeteria style food) relative to rats provided with chow
(Maniam and Morris, 2010b). Eating hedonically pleasant food
during stress may dampen HPA axis activity through activation of
dopamine activity in the limbic area. Dopamine release is proposed
to act as negative feedback to the hypothalamus to inhibit further
release of CRH, a process involved in stress recovery in the HPA
axis that results in reduced corticosterone/cortisol levels.
Several studies have also demonstrated that increases in gluco-
corticoid levels promote the intake of palatable foods (Bell et al.,
2000; Bhatnagar et al., 2000). In a recent prospective study exam-
ining almost 7000 adolescents, greater stress-related eating was
observed in girls, and the so-called ‘stress-driven’ eaters had a
higher prevalence of overweight, obesity and abdominal adipos-
ity compared to those who did not eat in response to stress
(Jaaskelainen et al., 2014). A systematic review examining the
relationship between stress and obesity reported that positive asso-
ciations between stress and body weight were more often identified
in females (Moore and Cunningham, 2012). The possibility of gen-
der specific effects warrants further investigation. Another recent
study of more than 65,000 older (>50) adults reported that higher
levels of perceived stress were associated with greater intake of
high fat snacks and fast foods (Barrington et al., 2014). In summary,
it appears that stress induced positive energy intake is associated
with increased risk of developing obesity and its associated diseases
such as diabetes and cardiovascular disease, which have become a
primary public health concern.
3.1. Early life stress and other influences on eating
behavior/obesity risk
In addition to the impact of stressful events in adulthood, grow-
ing evidence points to the possibility of long term metabolic effects
of an adverse early environment. Severe emotional or physical
stress early in life may have long lasting effects, increasing the risk
of depression and a range of psychiatric disorders. Early disruption
of the mother–child relationship, child abuse, neglect, or exposure
to war, modifies stress pathways and elevates plasma corticoste-
rone levels in later life (Cohen et al., 2006; Heim and Nemeroff,
1999). Adverse childhood experiences have also been associated
with increased risk of body weight gain across the lifespan. Cross
sectional analysis of a large UK sample showed that maternal stress
was associated with early childhood obesity (odds ratio 1.62 at age 3
years), which was taken to be mediated by an influence on the early
life environment of the child (Ramasubramanian et al., 2013). Chil-
dren who experienced many negative life events were more likely
to be obese at 15 years of age (Lumeng et al., 2013). A prospec-
tive cohort study of female victims of sexual abuse between the
ages of 6 and 27 years reported increased incidence of obesity dur-
ing young adulthood (Noll et al., 2007). Adversity during early life
and adolescence in the form of parental conflict or parental sepa-
ration increased the risk of later life obesity (D’Argenio et al., 2009;
Gunstad et al., 2006) and markers of metabolic risk (Danese et al.,
2009). Similarly, experience of a range of early life stressors was
positively correlated with increased adult BMI in men, independent
of mental health condition (Gunstad et al., 2006).
Alterations in diet during fetal development or the postna-
tal period can constitute a form of stress. Changes in overall
food availability (malnutrition or overnutrition), or limitations in
selected nutrients (macronutrient and mineral deficiency) dur-
ing fetal or early postnatal development alters cell structure and
metabolism, which reprograms stress responsiveness (HPA axis
activity) (Barker, 1998; Poore et al., 2010; Schmidt et al., 2008).
Early life stress induces hypersecretion of glucocorticoids via
hyperactivation of HPA axis (Lehmann and Feldon, 2000; Lippmann
et al., 2007; Macri et al., 2008; Maniam and Morris, 2010a,b). This
physiological response exposes peripheral tissues to high levels
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of glucocorticoids. At pharmacological doses, glucocorticoids have
anti-inflammatory actions. However, chronic exposure to high lev-
els of glucocorticoids may elicit metabolic derangements including
accumulation of abdominal fat, dyslipidemia, and insulin/glucose
intolerance later in life (Maniam et al., 2014; Maniam and Morris,
2010a,b; Paternain et al., 2013). For example, chronic consump-
tion of high fat diet post-weaning in rats previously exposed to
early life stress led to a doubling of plasma insulin levels versus
rats exposed to early life stress but consuming only chow (Maniam
and Morris, 2010a,b). Rats subjected to early life stress and consum-
ing a diet deficient in omega-3 had elevated plasma insulin levels
and impaired insulin sensitivity compared to rats exposed to early
life stress but fed a control diet (Bernardi et al., 2013). Despite the
known effects of early life stress on HPA axis activity in later life,
little is known regarding how early life stress exposure alters hypo-
thalamic feeding neuropeptides. Feeding is regulated by orexigenic
and anorexigenic hypothalamic neuropeptides, and is also influ-
enced by HPA axis activity and circulating glucocorticoids (Krysiak
et al., 1999; Maniam and Morris, 2012). Stress has stimulatory
effects on hypothalamic NPY expression (Dean and White, 1990;
Goto et al., 2006; Sato et al., 2005). We recently proposed that early
life stress exposure may alter hypothalamic feeding neuropeptide
expression which may partly mediate increased food intake and
adiposity in later life (Maniam et al., 2014).
It is likely that other factors such as 11␤-hydroxysteroid dehy-
drogenase type I (11␤-HSD1) also play a role in mediating the
metabolic effects of early life stress (Maniam et al., 2014). In addi-
tion to circulating cortisol, tissue-specific glucocorticoids play an
important role in regulating metabolic function (Morgan et al.,
2014). Intracellular levels of glucocorticoids are tightly regulated
by 11␤-HSD1, which converts inactive glucocorticoid to active glu-
cocorticoid in insulin sensitive tissues such as liver, adipose tissue
and skeletal muscle (Tomlinson et al., 2004). Chronically increased
glucocorticoid action as a result of elevated 11␤-HSD1 activity is
associated with obesity, insulin resistance, type 2 diabetes melli-
tus (Morton et al., 2004; Rask et al., 2001; Tomlinson et al., 2008).
Increased 11␤-HSD1 mRNA expression was observed in visceral
and subcutaneous fat of obese versus lean women and men (Alberti
et al., 2007; Paulsen et al., 2007). Taken together, these studies sug-
gest a role of increased glucocorticoid availability, particularly in
adipose tissue, in promoting obesity.
3.2. Rodent model of early life stress–maternal separation
Rodent models have shown that early life stress induced by
maternal separation may also affect feeding behavior and influ-
ence metabolic disease risk. In our hands rats appear to consume
similar amounts of energy, independent of diet, following early
life stress induced by maternal separation, but those consuming
a high fat/high sugar diet had increased circulating insulin relative
to non-stressed controls, suggesting long term metabolic conse-
quences of early stress (Maniam et al., 2014; Maniam and Morris,
2010a,b). Others have reported changes in food intake following
maternal separation that were only apparent in the presence of a
stressor in later life, such as isolation stress or restricted feeding.
For example, post-weaning isolation following maternal separation
resulted in weight gain and increased food intake (Ryu et al., 2008).
In an earlier study, maternal separation was associated with greater
rebound hyperphagia following restricted feeding (2 h daily for a
period of 6 days) in female but not male rats (White et al., 1990).
Stress during pregnancy was also shown to affect metabolic func-
tion of offspring. Exposure to chronic mild stress during the 3rd
week of gestation increased fat mass in those offspring consuming
high fat/high sucrose diet, suggesting that maternal stress during
development enhances the predisposition to obesity induced by an
unhealthy diet (Paternain et al., 2013). Further work is required to
Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
5
determine how exposure to adverse early life events may impose
metabolic deficits on offspring.
In summary, stress in adulthood may lead to changes in feeding
behavior that increase the risk of metabolic disease, and emerg-
ing evidence points to impacts of early life experience, induced by
altered nutrition, or stress exposure in utero or early in life, on off-
spring food consumption or metabolism, that may increase the risk
of developing obesity in later years.
4. Effects of high energy diets on cognition
Cognitive impairments are one of the many adverse health
effects of the chronic consumption of high energy diets (Alencar
et al., 2010; Lu et al., 2012). However, an important new challenge
has emerged; these cognitive deficits can occur rapidly and in some
cases, independently of the metabolic and cardiovascular disorders
associated with obesity.
A number of cross-sectional, prospective and longitudinal stud-
ies have found associations between diets rich in saturated fat
and/or sugar with cognitive deficits after adjusting for demographic
and vascular factors. Higher saturated fat intake in mid and later life
has been associated with worse global cognitive function, impair-
ments in prospective memory, memory retrieval and flexibility,
as well as an increased vulnerability to both normal age related
cognitive decline and neurological diseases including dementia
and Alzheimer’s disease (Eskelinen et al., 2008; Grant et al., 2002;
Solfrizzi et al., 2010). Likewise, people whose diet contains exces-
sive amounts of refined sugar are more likely to have lower overall
cognition in middle and older age (Ye et al., 2011). Roberts et al.
(2012) found that the risk of mild cognitive impairment or demen-
tia was increased in elderly subjects who derived a high percentage
of their energy from carbohydrates, but was reduced in those who
derived a high percentage of energy from fat and protein. The effects
of diet on cognition are not confined to adults. Abargouei et al.
(2012) reported that higher sugar intake in school-aged children
was inversely related to non-verbal intelligence including spatial
memory as measured by Raven’s Progressive Matrices
4.1. Evidence for effects of high energy diets on human cognition
Only a handful of studies have experimentally controlled their
participants’ diet and measured the effects on cognition. As accu-
rate food consumption data is notoriously difficult to obtain outside
an experimental context, such studies are important as they allow
causal inferences to be drawn. In healthy, young adult males, a 5 day
high fat diet (75% of energy) was sufficient to impair attention and
speed of retrieval, and to depress mood, as measured by the Cog-
nitive Drug Research assessment battery (Holloway et al., 2011).
Similarly, in sedentary male subjects (25–45 years, <2 h/week phys-
ical exertion), 7 days of a high fat diet (74% of energy) decreased
reaction times and attention (Edwards et al., 2011). Moreover, eat-
ing a single high glycemic meal before testing impaired memory
performance, but increased vigilance, in normal weight undergrad-
uate women (Nabb and Benton, 2006), school aged children (Micha
et al., 2011) and in adults with well-controlled type 2 diabetes
(Papanikolaou et al., 2006). A longer term study in children, how-
ever, found no behavioral or cognitive effects of 3 weeks of sucrose,
saccharin or aspartame sweetened diets, regardless of whether the
children were reported to respond adversely or normally to sugar
by their parents (Wolraich et al., 1994).
A different experimental approach was taken in a study by
Francis and Stevenson (2011). In Experiment 1, participants com-
pleted neuropsychological tests and questionnaires that assessed
their saturated fat and refined sugar intake. Food, not BMI or
general cognitive function, was found to be the best predictor
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Fig. 1. High fat diet increases oxidative stress (OS) in the hippocampus, contributing
to decreased levels of neurotrophins such as BDNF, and downstream effects, includ-
ing reduced phosphorylation of synapsin 1, growth-associated protein (GAP)-43 and
(cAMP response element-binding protein) CREB.
Taken from Wu et al. (2004) with permission.
of subsequent performance in the hippocampal-dependent ver-
bal paired associate task and the logical memory subtests of the
Wechsler memory scale revised. Experiment 2 then compared a
subset of these participants, matched on factors such as BMI and
age, but who reported the highest and lowest intakes of saturated
fats and refined sugars. Individuals with higher saturated fat and
refined sugar consumption performed worse on the hippocampal-
dependent memory test (visual reproduction, logical memory, and
verbal paired associates) and were less accurate at recalling what
they had previously eaten in an experimental snack meal 60 min
prior than those who consumed low amounts of fat and sugar.
Importantly, these results were obtained in a young population
with a mainly BMI healthy range, no comorbid medical conditions,
such as diabetes or cardiovascular disease, and who did not dif-
fer on measures of general cognitive function such as attention
and concentration (digit span subtest of the Wechsler adult intel-
ligence scale – fourth edition) and general intelligence (National
Adult Reading Test). These experimental results in humans there-
fore suggest that the effects of fat and sugar on memory may occur
independently of any effects on body weight or general health.
4.2. Effects of high energy diets on learning and memory in
rodents
Studies with rodents have confirmed that the long-term intake
of high fat/high sugar diets impair cognition. These impairments
are especially evident in tasks which require the hippocampus and
surrounding cortices, such as the Morris water maze where rodents
must use spatial relations among cues to navigate to a hidden plat-
form (Heyward et al., 2012; McNay et al., 2010). Impairments have
also been reported on a number of other maze tasks, including
the T-maze (Farr et al., 2008; Pistell et al., 2010), the radial arm
maze (Murray et al., 2009) and the four arm maze (Valladolid-
Acebes et al., 2011), as well as hippocampal independent operant
lever pressing tasks (Farr et al., 2008) and conditioned discrimi-
nation (Greenwood and Winocur, 1990, 1996, 2005; Winocur and
Greenwood, 1999, 2005). Some of these studies have also identified
changes in the hippocampus which may mediate the link between
obesity and cognitive deficits including oxidative stress, neuroin-
flammation, as well as decreased levels of neurotrophic factors
(Fig. 1).
There is also emerging evidence that high energy diets can
impair memory in advance of substantial increases in body weight.
Please cite this article in press as: Morris, M.J., et al., Why is obesity such a problem in the 21st century? The intersection of palatable food,
cues and reward pathways, stress, and cognition. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.12.002
We recently showed that rats exposed to a cafeteria diet containing
many of the foods eaten by people with or without a 10% sucrose
solution, or a regular chow diet with a 10% sucrose solution were
impaired on a hippocampal-dependent place recognition task after
5, 11 and 21 days (Beilharz et al., 2014), however they displayed
comparable performance to control rats on a perirhinal dependent
object recognition task (Aggleton and Brown, 2005), suggesting
selective hippocampal deficits. Body weight differences had not
emerged after only 5 days of diet exposure when the impair-
ments were first evident and therefore, obesity was not a causal
factor. Hippocampal inflammation (TNF-␣ and IL-1␤ mRNA) and
oxidative stress (NRF-1 mRNA) markers were significantly elevated
after 1 month of exposure to either cafeteria diet with or without
sucrose or chow supplemented with sucrose, and these markers
were negatively correlated with performance on the place recog-
nition task (see Fig. 2). Hippocampal neurotrophic factors such as
brain-derived neurotrophic factor (BDNF) were not affected by the
month long exposure to these diets (Beilharz et al., 2014). Davidson
et al. (2013) demonstrated that rodents appear to recover from the
acute effects of western diet on cognition, and that high ketone
bodies maybe protective (Davidson et al., 2013). Interestingly, a
western diet was also shown to impact on hypothalamic inflam-
mation, eliciting early increases in inflammatory markers in the
mediobasal hypothalamus, which subsided before returning after
one month’s exposure (Thaler et al., 2012). While several stud-
ies now indicate that cognitive deficits may precede the onset of
obesity, identification of the relative impact and interrelationships
between adiposity, body weight and glucose regulation requires
more investigation. Taken together these results show that short-
term exposure to diets high in fat and sugar, or just high in
sugar, impairs aspects of cognition, suggesting that the modern
diet may rapidly produce impairments in people, including children
(Davidson et al., 2005).
These results are important because the hippocampus is not
just involved in learning and memory, but also in the control of
eating. The hippocampus contains receptors for hormones and adi-
posity signals, such as ghrelin and leptin, and hippocampal neurons
receive input from multiple brain regions critical for food intake.
Previous studies have shown that damage to the hippocampus
can increase food intake and result in body weight gain (Davidson
et al., 2009). Moreover, reversible inactivation of the hippocam-
pus results in decreased latency in meal onset, increased meal size
and a disrupted relationship between meal size and the interval
to the next meal (Henderson et al., 2013). Given that overeat-
ing can impair hippocampal function, excessive food intake may
contribute to body weight gain by interfering with hippocampal-
dependent higher-order learning and memory processes. These
processes include episodic memory, for example, remembering
where, when and what we have previously eaten. This may create a
vicious cycle with high energy diets causing hippocampal dysfunc-
tion which leads to a further overeating of the foods that caused
the dysfunction in the first place (Davidson et al., 2005, 2007).
5. Summary and future directions
Unless the current obesity trend is halted, the burden of chronic
disease in future generations will lead to a crisis in health and
economic systems around the world. It is of vital importance to
understand how the modern diet, the foods that we manufac-
ture, plus the prevailing stressful environment influence individual
food choices, potentially driving overconsumption of energy. The
omnipresence of cues promoting intake of palatable food, coupled
with the rewarding aspects of these appealing, heavily processed
foods may increase the motivation to eat to excess. Stress also
affects food choice. People may increase the amount of high fat/high
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M.J. Morris et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
Fig. 2. Relationship between hippocampal TNF-␣ mRNA expression and exploration ratios on the object (left) and place (right) recognition tasks after 20–21 days on the
regular (open circle), cafeteria with sugar (closed circle), regular with sugar (open triangle) and cafeteria alone (solid square) diets. n = 5–8 rats per group. TNF-␣ mRNA was
negatively correlated with exploration ratios for the place task.
Reproduced from Beilharz et al. (2014) with permission.
sugar food consumed in response to a stressor, making stress
a risk factor for the development of obesity in vulnerable indi-
viduals. Emerging evidence linking severe early life stress and
later metabolic disorders needs additional work to identify the
mechanisms underlying this association. Animal and human data
indicate that high fat/high sugar foods can also impair some forms
of hippocampal-dependent memories, which may further impair
appetite control by undermining the processes involved in seeking
and consuming food. Further research is also necessary to deter-
mine the mechanisms through which obesity and its comorbidities
may exacerbate cognitive impairments, particularly with aging,
where optimal nutrition is critical to preserve cognitive function.
Understanding the mechanisms underpinning the impact of other
preventive/supportive strategies such as increasing physical activ-
ity, should also be a priority. Such information is vital to provide
important insights into the drivers of obesity and to enable novel
interventions to ameliorate the epidemic.
In the 21st century, obesity should be viewed not only as a
metabolic disorder, but as a multifactorial disease. Thus, strate-
gies that focus on modulation of the reward system, reduction of
stress reactivity and reverse compromised hippocampal function
may be more effective than the currently available pharmacolog-
ical approaches typically targeting appetite suppression. Overall,
understanding the factors that increase the vulnerability of indi-
viduals to develop obesity is essential in developing more effective
treatments. Of course, providing education and support to indi-
viduals and populations in strategies for promoting healthy food
intake, and appropriate physical activity, are also of critical impor-
tance in the prevention of obesity.
Acknowledgement
This work was supported by NHMRC Project grant 1023073
awarded to MJM and RFW.
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