REVIEWS

Hormonal and neural mechanisms of food

reward, eating behaviour and obesity
Susan Murray, Alastair Tulloch, Mark S. Gold and Nicole M. Avena
Abstract | With rising rates of obesity, research continues to explore the contributions of homeostatic and
hedonic mechanisms related to eating behaviour. In this Review, we synthesize the existing information on
select biological mechanisms associated with reward-related food intake, dealing primarily with consumption
of highly palatable foods. In addition to their established functions in normal feeding, three primary peripheral
hormones (leptin, ghrelin and insulin) play important parts in food reward. Studies in laboratory animals
and humans also show relationships between hyperphagia or obesity and neural pathways involved in
reward. These findings have prompted questions regarding the possibility of addictive-like aspects in food
consumption. Further exploration of this topic may help to explain aberrant eating patterns, such as binge
eating, and provide insight into the current rates of overweight and obesity.
Murray, S. et al. Nat. Rev. Endocrinol. advance online publication 24 June 2014; doi:10.1038/nrendo.2014.91

Introduction
The rise in the prevalence of obesity worldwide has
prompted widespread research to improve understand­
ing of this phenomenon. A major focus of such research
is the contribution of overeating, which can produce a
positive energy balance and result in body weight gain.
Homeostatic mechanisms involved in promoting and
inhibiting feeding behaviour have been studied, includ­
ing those related to gut hormones (for example, ghrelin,
cholecystokinin, insulin and leptin) and neural activ­
ity in relevant brain regions.1 Additionally, research­
ers have investigated how hedonic eating, which is
eating based on pleasure rather than energy needs,
affects neural mechanisms associated with reward and
perhaps perpetuates this type of eating behaviour.2 This
line of inquiry has yielded somewhat surprising find­
ings, with preclinical studies showing behavioural and
neurochemical overlap between the effects of overeating
New York Obesity highly palatable foods and addiction to drugs, such as
Research Center,
Department of
alcohol and cocaine.3–5 Evidence from clinical studies
Medicine, Columbia supports the concept of food addiction,6,7 which could
University College of have important implications for understanding patterns
Physicians and
Surgeons, P&S Box 30 of overeating, eating disorders characterized by binge
DOM/NYORC, eating and the rates of overweight and obesity in specific
630 West 168th Street,
New York,
subgroups of people.8
NY 10032‑3702, USA The goal of this Review is to present a clear picture
(S.M., A.T., N.M.A.). of the existing information regarding homeostatic
Department
of Psychiatry, College of and hedonic factors related to eating behaviour and
Medicine, University to highlight areas that might benefit from further
of Florida, McKnight
Brain Institute,
research. Although homeostatic and hedonic physio­
1149 SW Newell Drive, logical systems are often described as contrasting, one
L4‑100, Gainesville, of the primary purposes of the current Review is to
FL 32610, USA
(M.S.G.). discuss emerging data that suggest strong interactions
Correspondence to:
N.M.A. Competing interests
na2574@columbia.edu The authors declare no competing interests.
between the two systems. Additionally, we provide
data from preclinical and clinical studies to assess
the possible p­rogression from food reward to signs of
food addiction.
Reward-associated endocrine factors
Endocrine factors have important roles in appetite-
related signalling.9,10 More than 20 regulatory gut and
adiposity hormones have a wide array of functions
related to feeding. 10–13 A comprehensive analysis of
these factors is beyond the scope of this Review; here,
we discuss how select endocrine factors interact with
brain reward systems and their potential relationships
with alterations in body weight and hedonically driven
food intake (Figure 1).
Leptin
While leptin’s role in homeostatic mechanisms is well
documented, less is known about its connection to the
reward system. Leptin receptors are found on dopa­
minergic neurons in the ventral tegmental area (VTA)
projecting into the nucleus accumbens (NAc). 14,15
Admin­istration of leptin is associated with reduced food
intake via homeostatic and hedonic mechanisms.14,15 In
rats, administration of leptin led to a decrease in the
firing rate of VTA dopaminergic neurons and to reduced
food intake that was reversible after knockdown of the
leptin receptor by RNA interference.15 Locomotor activ­
ity and sensitivity to highly palatable food, assessed by
free choice of water versus sucrose and of chow versus
high-fat food, also increased. 15 In leptin-deficient
ob/ob mice, diminished dopamine concentrations and
evoked dopamine release are observed in the NAc.14
Interestingly, a diminished locomotor response to
amphetamine is also observed, which is restored

NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  1

© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS

Key points in dopamine synthesis, 20 in the VTA and, therefore,

■■ The rise in the prevalence of obesity has prompted numerous research efforts
dedicated to better understanding the mechanisms underlying this trend
■■ A major focus of such research is the contribution of overeating, which can
produce a positive energy balance and result in body weight gain
■■ More recently, select endocrine factors associated with food intake and body
weight have been shown to interact with neural systems of reward
■■ Preclinical and clinical studies suggest that food reward and alterations in
reward pathways may progress to food addiction
to normal after administration of leptin in the VTA
and NAc.14 These results must be interpreted cautiously
because this study used a modified animal strain and,
therefore, might reflect compensation related to defects,
especially during the developmental period, rather than
normal physiological function.16
The specific effects of leptin on the mesolimbic dopa­
mine system seem to involve multiple mechanisms. For
instance, receptors in the VTA and lateral hypothalamic
area (LHA) have distinct leptin-activated pathways.
Leptin activation of an alternative JAK‑2 pathway in the
VTA,17,18 rather than the usual mTOR or PI3K pathways
in the hypothalamus,18 was associated with reduced food
intake, posited to be due to the action of leptin on dopa­
minergic neurons,18 although this observation remains to
be confirmed. Injection of leptin in the LHA led to the
activation of leptin receptors on neurons (whether they
were dopaminergic or GABA-ergic is unclear), which
was associated with reductions in food intake and body
weight.19 Additionally, leptin substantially increased the
activity of tyrosine hydroxylase, the rate-limiting enzyme
dopamine content in the NAc was modulated by regu­
lation of VTA dopamine production but not release. 19
The hedonic value of food was not increased, which
supports dopamine release being regulated through
different mechanisms.19
In mice with a knockout of leptin receptors on neur­
ons that express neurotensin in the LHA, the activity
of d­opamine active transporter (DAT), which facilitates
dopamine reuptake, was decreased in the NAc com­
pared with that in controls and locomotor activity was
reduced. 21 Dopamine levels and activity of tyrosine
hydroxylase in the VTA did not change. These mice
exhibited early-onset obesity and increased feeding,21
particularly when fed highly palatable foods.22 Neurons
in the LHA, therefore, seem to contribute to the inhibi­
tion of food reward and are likely to be dopaminergic
neurons. Intra-LHA leptin administration in these
mice, however, leads to decreased expression of tyrosine
hydroxylase in the VTA and increased feeding.22 These
findings are consistent with the notion that leptin signal­
ling via the LHA neurons expressing leptin and neuro­
tensin receptors is needed to suppress food intake and
modulate dopamine function. Lastly, alternative mecha­
nisms regarding the action of leptin on leptin receptors
located on dopaminergic neurons in the LHA have been
proposed on the basis of findings from ex vivo experi­
ments, demonstrating that the precise action of leptin in
this brain region remains unresolved.23,24
Other rodent studies suggest that leptin resist­
ance in reward pathways occurs independently of that

Insulin Leptin

ARC Ghrelin LHA Body

weight
Food intake VTA NAc
Food
intake
Reward
threshold

Dopamine
levels
DAT

Dopamine Firing rate TH activity Food Food MOR DRD1 Locomotor

release of dopaminergic and dopamine intake intake expression and DRD2 activity
neurons content activation

Sucrose
Firing rate responding
of dopaminergic and chow
neurons intake

Figure 1 | Potential relationships between endocrine factors and chemical signalling pathways, and effects on feeding
behaviour. Leptin decreases body weight and food intake through signalling in the LHA, and increases TH activity, increases
dopamine content (but not release), decreases the firing rate of dopaminergic neurons, and decreases food intake through
signalling in the VTA. Ghrelin influences signalling in the VTA, which increases food intake and expression of μ‑opioid
receptors (and subsequent responses to sucrose and chow intake). Ghrelin also induces chemical signalling from the VTA
to the NAc, which increases activation of DRD1 and DRD2 and leads to increased dopamine levels (and subsequent
locomotor activity). Insulin increases food intake via signalling in the ARC and the VTA. Additionally, by means of the VTA,
insulin increases the reward threshold, DAT activity (and subsequent dopamine release) and the firing rate of dopaminergic
neurons. Abbreviations: ARC, arcuate nucleus of the hypothalamus; DAT, dopamine active transporter; DRD1, dopamine D 1
receptor; DRD2, dopamine D2 receptor; LHA, lateral hypothalamic area; MOR, μ‑opioid receptor; NAc, nucleus accumbens;
TH, tyrosine hydroxylase; VTA, ventral tegmental area.

2  |  ADVANCE ONLINE PUBLICATION www.nature.com/nrendo

© 2014 Macmillan Publishers Limited. All rights reserved

associated with energy homeostasis mechanisms (for
example, in the leptin–melanocortin pathway). The
anorexigenic effect of leptin in reward-­a ssociated
brain regions, notably the VTA, is attenuated in obese
rats receiving a high-fat diet, 25 but this effect is not
seen in dopamine-resistant rats with diet-induced
obesity fed the same diet or in rats fed a low-fat diet.
Moreover, sustained leptin overexpression in either the
VTA or the medial basal hypothalamus (specifically,
the arcuate nucleus) leads to leptin resistance in both
regions, regardless of the location of leptin injection, in
animals fed a high-fat diet.26 This finding is consistent
with those from previous experiments, in which wide­
spread leptin resistance followed chronic central leptin
overexpression, whereas leptin resistance in rats with
diet-induced obesity is seen only in the VTA and arcuate
nucleus of the hypo­thalamus.27 These elegant experi­
ments support the likelihood that desensitization of
reward regions to leptin could lead to o­verconsumption
of highly p­alatable food.
The influence of leptin on food reward in humans is
well established. Functional MRI shows activation of
reward areas (especially the dorsal striatum and orbito­
frontal cortex) in response to food cues in individuals
with obesity, and the degree of activation increases with
exposure to images of high-calorie food and is indepen­
dent of satiation status.28 Activation of the ventral stria­
tum induced by food cues positively correlated with
leptin concentrations and BMI, which suggests that
reward systems conventionally inhibited by leptin are
d­esensitized to the hormone’s effect.29
Low total fat mass and concomitant reductions in
leptin levels instigated by weight loss have been associ­
ated with increased brain activation in response to food
cues in several limbic regions, especially the brainstem,
parahippocampal gyrus and culmen, all of which are
involved in homeostatic and reward functions related
to food intake.30 After weight loss, leptin administra­
tion reduces the activation of these areas compared with
placebo administration, which suggests sensitization of
reward systems to leptin and a reduction in the perceived
hedonic value of food.30 In a related study, leptin injec­
tion following weight loss was associated with reduced
food-cue-induced activation of reward system regions,
including the hypothalamus, NAc and the orbito­frontal
cortex, compared with activation in people not treated
with leptin.31
In summary, the evidence indicates that leptin acts
primarily in the VTA and LHA to decrease food intake.
In the VTA, leptin modulates dopamine activity by redu­
cing the firing rate of dopaminergic neurons and altering
the activities of metabolites associated with dopamine
function, such as tyrosine hydroxylase and DAT. In the
LHA, leptin acts on neurons that express leptin recep­
tors, which in turn alters the activities of several dopa­
mine metabolites. However, the precise role of leptin in
the LHA remains unclear, as findings are inconsistent.
Finally, leptin resistance seems to alter the normal func­
tioning of homeostatic and hedonic p­rocesses in brain
regions involved in feeding behaviour.
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  3
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Ghrelin
Ghrelin, the only known orexigenic gut hormone, is
secreted from the stomach and primarily activates
neurons that secrete neuropeptide Y and Agouti-related
protein, which leads to increased food intake and pro­
motion of weight gain.11 To explain the hyperphagic
tendencies in certain individuals with obesity despite
reduced ghrelin concentrations,32–35 researchers have
begun to study whether ghrelin modulates components
of the meso­limbic reward system. Ghrelin receptors are
expressed on GABA-ergic and dopaminergic neurons in
the VTA and the substantia nigra.36 In animal models,
expression of ghrelin mRNA and concentrations of
ghrelin in serum are reduced by intake of sucrose and
high-fat diets, yet the animals are unable to control
overeating.37 Ghrelin has been purported to increase the
reward value of high-fat diets in mice, as evidenced by
conditioned place preference and operant condition­
ing tasks.38 Ghrelin seems to exert its effect on reward
mechanisms in the VTA.39 Intra-VTA administration of
ghrelin is associated with increased palatable food intake,
although not chow intake, as well as increased dopa­
mine concentrations in the NAc and locomotor activity,
whereas these effects were not seen in ghrelin-receptor
knockout mice.40 Specifically, ghrelin is thought to incen­
tivize food intake by increasing acetyl­choline levels in
the VTA,41 increasing dopamine levels in the NAc,41
activation of dopa­minergic projections from the VTA to
the NAc,41,42 and activation of dopamine D1-like and D2
receptors in the NAc.42 Additionally, sucrose-­motivated
operant behaviour was reduced after the effects of endo­
genous and VTA-administered ghrelin were ablated by
the adminis­tration of D1-like and D2 receptor antago­
nists into the NAc shell 42 or by the administration of
ghrelin-­receptor antagonists.43 This effect was not seen
for chow. In addition to its effect on the release of dopa­
mine and acetyl­choline, ghrelin also alters the expres­
sion of a wide array of dopamine (D1, D3 and D5) and
acetylcholine (nAChRβ2 and nAChRα3) receptors in the
VTA and NAc.43
The reward-related actions of ghrelin are not limited
to those on dopamine and acetylcholine; ventricular and
intra-VTA administration of ghrelin has been associ­
ated with increased μ‑opioid-receptor expression in the
VTA, which induced sucrose-motivated behaviour and
increased chow intake,44 effects that were blocked when
the μ‑opioid receptor antagonist naltrexone was admin­
istered within the VTA.44 In contrast to these findings,
systemically administered ghrelin followed by intake of
palatable food seemed to change which opiod receptor
was predominantly activated, from activation of μ‑opioid
receptors to activation of κ‑opioid receptors, which
seems to inhibit dopamine release.45
Notably, clinical research has shown significantly
increased levels of ghrelin following the consumption
of food for pleasure in healthy sated individuals.46,47 If
ghrelin enhances the rewarding value of palatable foods
and the release of this hormone is not attenuated with the
consumption of these foods, ghrelin may act in conjunc­
tion with brain reward systems to promote overeating of
REVIEWS
palatable foods.38 However, further research is needed
in this area, as previous experiments using a laboratory
animal model show reduced ghrelin levels with palatable
food diets.37
Overall, ghrelin seems to enhance the reward­
ing value of food by acting on neurons in the VTA to
release acetyl­choline, which in turn increases activation
of dopaminergic projections from the VTA to the NAc
and increases concentrations of dopamine and activa­
tion of dopamine receptors in the NAc. Furthermore,
evidence suggests that ghrelin affects opioid recep­
tors involved in food reward. While clinical studies
are needed to settle discrep­ancies between animal and
human findings, ghrelin clearly has an important role in
food reward systems.
Insulin
In addition to regulatory functions, insulin exhibits an
array of effects on brain functions, including mecha­
nisms involved in homeostatic and hedonic feeding.48
Like leptin, insulin receptors are found on dopaminergic
neurons in the VTA,49 which indicates a potential role in
the reward system, although by precisely what mecha­
nisms remains unclear. In rodent models, administration
of insulin into the VTA or arcuate nucleus of the hypo­
thalamus is associated with decreased food intake,17,50
particularly of highly palatable foods. 51,52 However,
only intra-VTA administration of insulin elevates brain
reward thresholds (indicating reduced reward func­
tion),17 presumably by suppression of excitatory synaptic
transmission,50 including activity of μ‑opioid receptors.51
Insulin also seems to reduce somatodendritic dopamine
levels in the VTA by upregulation of DAT through
PI3K and mTOR signalling.52 Furthermore, mice with
inacti­vated insulin receptors in cells expressing tyro­sine
hydroxylase exhibit increased body weight and fat mass,
and hyperphagia. 53 In addition, insulin increases the
firing rate of 50% of dopaminergic neurons in the VTA,
probably by upregulation of DAT within VTA cells.53
In humans, fasting 54 and postprandial55 administration
of insulin reduces food intake, including that of highly
palatable foods.55 Moreover, increased insulin concen­
trations have been associated with reduced activation
of several bilateral brain regions, including the fusiform
gyrus and the limbic system, in response to images of
food.56 This evidence indicates decreased responsiveness
to food cues, which may assist in counteracting over­
consumption or urges to overeat. Collectively, insulin
seems to act to suppress food intake, at least in part by
altering neural reward systems.
Palatable food, reward and obesity
Dopamine-mediated reward systems
Preclinical studies
Studies in laboratory animal models have provided con­
siderable evidence to suggest that overeating, especial­ly
of high-fat and sugar-rich diets, and obesity affect
several components of the brain reward system. 3,57–60
These findings have led to debate about whether over­
eating and obesity are manifestations of addiction.3,61–65
4  |  ADVANCE ONLINE PUBLICATION
© 2014 Macmillan Publishers Limited. All rights reserved
The meso­limbic dopamine system has been a primary
focus for research into the relationship between food
intake and brain reward systems. Dopamine has long
been implicated in reward processes. Perhaps the strong­
est evidence of dopamine’s role in reward comes from
studies that show that rats will self-administer substances
that act like dopamine or stimulate dopamine release.66
Dopamine is released in the core and shell of the NAc
after highly palatable food intake or sucrose licking.67,68
Increased dopamine release is also seen in response to
aversive and stressful stimuli, 66 which indicates that
dopamine plays an important part in arousal or atten­
tion to salient stimuli and might be involved in learning
processes.66,69 Furthermore, dopamine has been impli­
cated in motor function,69 and it has been posited that
dopamine may be related to physical activity as a means
of achieving and maintaining energy homeostasis.70
Obesity-prone rodents, those with diet-induced obesity
and obese rodents fed a cafeteria diet consistently show
reduced basal extracellular dopamine concentrations in
the NAc relative to controls.71–74 Obesity-prone rats also
exhibit diminished dopamine release compared with
obesity-­resistant rats after eating a high-fat meal, even
before the onset of obesity.73 Furthermore, in slice prepa­
rations, electrically evoked dopamine release is lessened
in several brain regions—the NAc, dorsal striatum and
medial pre­frontal cortex—of obesity-prone and cafeteria-­
diet-fed obese rats. Mechanisms of dopamine release
might, therefore, be dysfunctional in these phenotypes
and hyperphagia and obesity might be secondary to
s­uppression of the dopaminergic system.71,72
This blunted dopamine activity is likely to be attri­
butable to reduced expression of several dopamine-
related metabolites,73 including vesicular monoamine
t­ransporter‑­2, tyrosine hydroxylase, DAT and dopamine
D2 receptors.71 Dopamine D1 receptor mRNA expres­
sion is downregulated in the NAc of obesity-prone
animals compared with obesity-resistant animals after
chronic consumption of high-fat, high-sugar diets, 75
whereas expression in the brainstem is upregulated.76
Availability of dopamine D2/3 receptors is reduced in the
dorsal striatum of rats given a choice between chow or
a high-fat diet 77 and in the NAc of rats given a high-fat,
high-sugar diet with a high fat-to-carbohydrate ratio.78
Additionally, high-fat diets are associated with reduced
DAT expression and function, thereby decreasing dopa­
mine efflux.79 Moreover, in obesity-prone animals, the
levels of dopamine metabolites remain low following
systemic administration of fat emulsion, an effect that is
not seen in their obesity-resistant counterparts.73
Many studies have examined the relationship between
the dopamine D2 receptor and food intake behaviour.
Therefore, in this Review we focus primarily on this dopa­
mine receptor. Dopamine D2 receptors are downregulated
in the striatum of obese rats fed a cafeteria diet4 and in
the hypothalamus of rats with diet-induced obesity. 80
More­over, a high-fat, high-sugar diet was associated
with reduced dopamine D2 receptor mRNA expression
in the brainstem of rats76 and sustained d­ownregulation in
the NAc.75
www.nature.com/nrendo

In animal studies of illicit drug use, reduced availabil­
ity of dopamine D2 receptors in the striatum before drug
use has been associated with increased drug intake.81
This characteristic could, therefore, be a predisposing
factor for increased intake of alternative substances that
activate the brain reward system, such as highly palat­
able food. Findings in Otsuka Long–Evans Tokushima
fatty rats, which have a spontaneous mutation that causes
overeating-­induced obesity, contrast with this hypothesis.
These rats show a strong preference for high concentra­
tions of sucrose and exhibit lower dopamine D2 recep­
tor levels in the NAc shell in adulthood than controls.
However, dopamine D2 receptor levels were normal­
ized when these rats were pair-fed, suggesting that this
alteration is causally related to eating behaviour and/or
weight.82 Furthermore, knockdown of striatal dopamine
D2 receptors induces compulsive-type behaviour in rela­
tion to highly palatable food.4 Preclinical studies also
show greater impulsivity in animals with decreased avail­
ability of dopamine D2 receptors.81 Of note, dopamine D2
receptor knockout mice exhibit reduced chow intake and
body weight, increased leptin sensitivity and increased
basal energy expenditure compared with controls. 83
Although conflicting, these data were produced with
a transgenic model and, therefore, must be i­nterpreted
with caution.
Several experiments have used dopamine D2 receptor
antagonists to try to elucidate the role of this receptor in
hyperphagic behaviours. Use of raclopride indicated
involvement of the receptor in sugar-stimulated hyper­
phagia, more so than that stimulated by fat; sucrose and
fructose intake were reduced after admini­stration of
the drug, whereas fat intake was unchanged.84,85 In rats
with intermittent access to fat, raclopride stimulated fat
intake, whereas it had no effect in rats that had daily
access to fat.84 Experiments with this antagonist have
produced conflicting findings with regards to sugar and
fat mixtures.86
The use of another dopamine D2 receptor antagonist,
eticlopride, seemed to reduce the reward incentive of food
in experiments of primary and secondary reinforce­ment
behaviour.87 Furthermore, tesofensine, a new drug being
investigated for weight loss, has been associated with
increased overall dopamine levels, reduced expression
of dopamine D2 receptors in the striatum and increased
striatal DAT binding.74,88 The reduced avail­ability of
dopamine D2 receptors, however, does not correlate with
weight loss or reduced caloric intake, which suggests that
the primary mechanism of tesofensine action is via an
increase in dopamine concentrations.88
Some research has been done to investigate whether
the alterations in the dopaminergic system seen in rats
with access to highly palatable food are related to behav­
ioural phenotypes resembling addiction.4,58,89–91 Relative
to obesity-resistant animals, obesity-prone animals
chronically fed a high-fat, high-sugar diet exhibit signs
of craving, increased anxiety and symptoms of with­
drawal when the diet is removed.92 Furthermore, animals
identified as exhibiting poor control over intake of
highly palatable food are more prone to food-induced
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  5
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
reinstatement of extinguished responding than are those
with standard food intake control, which indicates an
increased propensity for ‘relapse’ in certain animals.93
Furthermore, rats considered prone to binge eating will
endure higher magnitudes of electric shock in order to
obtain access to highly palatable food than those labelled
binge-resistant,5 indicating that for some animals highly
palatable food can be a powerful incentive for behaviour,
even despite hazardous consequences.
Intermittent access to and binge intake of sugar that
do not result in increased body weight have been associ­
ated with increased dopamine D1 receptor binding in
the NAc, 94 decreased dopamine D 2 receptor binding
in the NAc and dorsal striatum,94,95 and altered DAT
binding in specific regions.94 Furthermore, the increased
release of dopamine in the NAc after intake of highly
palatable foods is associated with increased dopamine
turnover in this region96 and increased concentrations
of DAT in the NAc and VTA.97 Bingeing rats also exhibit
decreased hypothalamic dopamine concentrations,98
whereas free access to a high-fat diet (independent of
obesity) reduces dopamine turnover in the NAc.99
Repeated chow meals and ad libitum sugar access are
associated with reduced dopamine release in the NAc,68,100
whereas chronic intermittent access to sugar, which
elicits bingeing behaviour, preserves the magnitude of
dopamine release in the NAc following sugar consump­
tion.100 This effect can also be achieved when animals
are given access to sweet-tasting food via sham feeding
procedures.101 Dopamine release also occurs in the NAc
when animals are sham fed high-fat corn oil,102 which
shows that effects on dopamine release are not limited to
sugar bingeing. Perhaps most importantly, the pattern of
dopamine release in the NAc of rats that repeatedly binge
eat sugar resembles that seen in drug abuse studies.3,103
Additionally, sugar-bingeing rats show physical signs
of withdrawal when they are administered the opioid
antagonist naloxone or are allowed no food.89,104 These
rats also exhibit increased responding for sugar following
a period of abstinence, which suggests craving and/or an
increased propensity to ‘relapse’.105 The concept of food
addiction remains controversial and many questions
remain, including whether specific types of food elicit
addiction-like neuroadaptations and behavioural profiles
and whether certain traditional symptoms of substance
dependence, such as withdrawal, can be observed and
measured in humans abstaining from certain foods.106,107
Clinical studies
Clinical studies have begun to explore the relationship
between dopamine, obesity and overeating. Several
studies have shown reduced availability of dopamine D2
receptors in the striatum of individuals who are over­
weight or have obesity;108–110 however, negative correla­
tions between body weight and dopamine D2 receptor
availability have not been entirely consistent.111 Down­
regulation of dopa­mine D2 receptors in response to
excessive extracellular dopamine concentrations, perhaps
caused by overeating and leading to dulled sensitivity of
the reward system, has been suggested to perpetuate
REVIEWS
patterns of overconsumption. Perhaps in line with this
theory, a link between reduced dopamine D2 receptor
availability in the dorsal striatum and perturbed eating
behaviour (increased emotional eating) has been shown
in healthy individuals.112
Greater increases in dopamine levels have been found
in the caudate nucleus of individuals with obesity and
binge eating disorder when seeing, smelling and tasting
food following administration of methylphenidate,
which blocks dopamine reuptake transporter, than in
participants with obesity who do not have binge eating
disorder.113 Binge eating disorder is recognized in the
Diagnostic and Statistical Manual of Mental Disorders
5th edition as a distinct diagnosis characterized by recur­
rent episodes (at least once per week for 3 months) of
excess food consumption during a limited time period,
which are accompanied by feelings of a lack of control
over eating. The authors of this study note that the
caudate is involved in the reinforcement of behaviours
directed towards obtaining a reward.113 Importantly, this
study found a positive association between increased
dopamine levels in the caudate and the severity of binge
eating.113 These findings suggest that this alteration in
dopamine function is less contingent upon increased
body weight and more directly related to the discrete
periods of overeating seen among those with binge eating
disorder, although the two conditions might overlap. By
contrast, striatal release of dopamine following methyl­
phenidate administration is negatively correlated with
the frequency of binge-eating episodes and vomiting
in patients with bulimia nervosa.114 Major differences
between characteristics in study samples (for example,
weight and eating disorder diagnoses) and the presence
of a food stimulus in these studies prevent definitive con­
clusions regarding the relationship between dopamine
and binge-eating behaviour.
Wilcox et al.115 provided evidence of a negative rela­
tionship between BMI and the ability to synthesize
presynaptic dopamine in the dorsal striatum. While the
precise meaning of this relationship remains unclear,
the authors suggest it might support claims that some
individuals overeat in an effort to compensate for
decreased reward function. Likewise, they suggest that
repeated overeating could lead to decreased reward
function, although further research would be needed to
establish this causal pattern.
As with preclinical studies, some clinical research has
been done to investigate whether findings of dopamine
dysfunction in individuals with obesity may be related
to addiction. Reduced dopamine D2 receptor avail­
ability in individuals with obesity has been associated
with decreased glucose metabolism in prefrontal brain
regions110 implicated in inhibition, hyperphagia and sali­
ence attribution, similar to observations made in people
with substance disorders. PET scans also demonstrate
negative correlations between impulsivity and availabil­
ity of dopamine D2/3 receptors in the striatum and mid­
brain of humans,116,117 a finding that might indicate the
mechanism by which dopamine D2 receptors are related
to both overeating and addiction.
6  |  ADVANCE ONLINE PUBLICATION
© 2014 Macmillan Publishers Limited. All rights reserved
Research on this topic has also focused on the relation­
ship between BMI and the TaqI DRD2*A1 allele. This
allele has been associated with decreased availability
of dopamine D2 receptors (although not in all studies),
impulsivity and several addictive disorders.118,119 It should
be noted that this allele is located downstream from the
gene that encodes the dopamine D2 receptor and its
precise function with regard to this receptor remains
unclear.120 With this limitation in mind, individuals
with obesity who carry the TaqI DRD2*A1 allele show
increased operant responding for food, and subsequently
consume more in feeding tasks.121 Additionally, indivi­
duals aged 21–40 years who carry the TaqI DRD2*A1
allele had greater BMI at baseline and regained more
weight during the maintenance phase of a weight loss trial
than did people without this allele.122 Stice et al.123 found
a negative association between BMI and neural activa­
tion in the caudate nucleus in participants who received
a highly palat­able food (chocolate milkshake) compared
with a tasteless solution, an effect that was exaggerated in
participants with the TaqI DRD2*A1 allele. Furthermore,
the presence of the TaqI DRD2*A1 allele moderated the
relationship between weight gain and neural activa­
tion when people consumed or imagined highly palat­
able food.123,124 More precisely, participants with the
TaqI DRD2*A1 allele, in whom activation of the frontal
operculum, lateral orbitofrontal cortex and striatum was
lower in response to imagining highly palatable foods
than unpalat­able foods or water, were more likely to gain
weight over time.123,124 Participants without the allele who
exhibi­ted increased neural activation of the same brain
regions when imagining highly palatable food were also
more likely to gain weight.123,124 The authors propose that
these results might indicate two mechanisms contribut­
ing to weight gain, namely that some individuals overeat
due to a hyper-responsive reward system (evidenced by
increased activation of certain brain regions) or a hypo­
responsive reward system (evidenced by reduced acti­
vation of certain brain regions). Davis and colleagues125
also point out that reward sensitivity, whether increased
or decreased, can be dynamic and fluctuate within an
i­ndividual over time.
While several studies have noted a relationship between
the TaqI DRD2*A1 allele, BMI and body fat content,126–128
some studies have shown no such association.120,122,129,130
The presence of this allele did not vary between obese and
lean groups in one study,131 but it was related to increased
disinhibition and bulimic symptoms, as measured by the
Bulimic Investigatory Test, Edinburgh. Bulimic symp­
toms were significantly more pronounced in individuals
with obesity who carried the TaqI DRD2*A1 allele than in
those without this allele, whereas symptoms did not differ
among lean participants regardless of TaqI DRD2*A1
status. Of note, however, the Bulimic Investigatory Test,
Edinburgh assesses several unhealthy attitudes and
behavi­ours related to food and it is unclear which of these
contributed to the overall finding. Other studies have
found that individuals without the TaqI DRD2*A1 allele
have increased binge-eating scores and, similarly, that the
TaqI DRD2*A1 allele is less likely to be found in people
www.nature.com/nrendo

with binge eating disorder than in those without.121,125
Further research in this area is needed to illuminate the
potential relationships between specific problematic eating
behaviours, weight, and TaqI DRD2*A1 allele status.
Opioid-mediated reward systems
Preclinical studies
The brain opioid system is another primary focus of food
reward studies. Alterations in μ‑opioid, δ‑opioid and κ‑
opioid receptors and opioid peptides are associated with
overeating and preference for highly palatable foods.132–135
Binge-like consumption of highly palatable foods is
associated with increased μ‑opioid receptor binding in
the cingulate cortex, hippocampus, locus coeruleus 94
and NAc shell. 94,136 Similarly, obesity-prone animals
exhibit increased expression of the μ‑opioid receptor
in the NAc.75 While expression of prepro­enkephalin,
a gene that encodes enkephalin peptides, is decreased
in a number of striatal regions following acute ingestion
of a highly palatable food,137 rats prone to overconsuming
a high-fat diet show increased hypothalamic expression
of enkephalin, particularly in the paraventricular nucleus,
NAc and central nucleus of the amygdala, even before
significant weight gain.134 Finally, decreased expression
of prodynorphin, the precursor of dynorphin (κ‑opioid
receptor ligand), has been found in the medial prefrontal
cortex following chronic consumption of highly palatable
foods.133 Taken together, altered expression and binding
patterns of enkephalin, prodyn­orphin and μ‑opioid
receptors in response to palatable food consumption
suggest a strong link between h­edonically driven feeding
and opioid function.
Opioid receptor agonists and antagonists are often
used to confirm that changes in the opioidergic system
are causally related to food intake behaviour. Injection
of the μ‑opioid receptor agonist (D-Ala2, N‑MePHe4,
Gly-ol)enkephalin into the NAc or the ventral medial
pre­frontal cortex of rodents is associated with increased
intake of highly palatable foods138–142 and increased pref­
erence for carbohydrate-rich foods.142 Butorphanol, a
μ‑opioid and κ‑opioid receptor agonist, is also associated
with increased intake of highly palatable foods in binge-
eating animals.143,144 Conversely, peripheral administration
of the nonspecific opioid receptor antagonist naltrexone
is associ­ated with decreased intake of highly palatable
foods,139,145 as is administration in the medial prefrontal
cortex 133 and NAc shell.146 Inhibition of highly palatable
food consumption is also observed after the adminis­
tration of naloxone, a μ‑opioid receptor antagonist, and
this effect is particularly pronounced in binge-eating
animals.84,86,147 As mentioned earlier, systemic administra­
tion of naloxone leads to withdrawal-like behaviour in rats
with a history of binge eating sugar.104,105 The use of a novel
μ‑opioid receptor antagonist, GSK15121498, prevented
food seeking and binge eating,148 and a little-used δ‑opioid
receptor antagonist, naltrindole, led to reduced consump­
tion of highly palatable foods.146 In rats, administration
of the μ‑opioid receptor antagonist β‑funaltrexamine
in the NAc lessened the development of diet-induced
obesity,149 presumably through diminished liking and
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  7
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
wanting of highly palatable foods.146,150 Finally, nalmefene,
a μ‑opioid and κ‑opioid antagonist, leads to reductions in
binge eating of highly palatable food in rats.151 Collectively,
the effects of activating and inhibiting opioid receptors
provide substantial evidence that the opioidergic system is
closely tied to the consumption of highly palatable foods.
Clinical studies
Research investigating the relationship between over­
eating and the brain opioid system in humans has been
largely limited to studies that assess the effects of pharma­
cological interventions targeting this system. For example,
nal­trexone reduced the perceived pleasantness of sweet,
fatty and protein-rich foods and led to reduced intake of
fat and protein in men.152 Although total food intake did
not differ between groups in this study, decreased food
intake and altered ratings of food pleasantness have been
documented following naltrexone administra­t ion in
humans.153,154 In other studies, how­ever, no effects of nal­
trexone have been observed on food pleasant­ness ratings
or intake.155
In binge eaters, naltrexone has led to reduced intake of
sweet and fat-rich foods, with no effect in normal eaters,
suggesting perturbations in the opioid systems of binge
eaters.156 Several, although not all,157 studies have found
that naltrexone and naloxone efficaciously reduced binge
eating or related factors (that is, binge duration and urge to
binge) in individuals with bulimia nervosa and binge eating
disorder.158–164 Interestingly, naltrexone-induced markers of
opioidergic tone (increases in cortisol levels and nausea)
are associated with increased emotional eating and binge
eating, and increased adiposity.165 These responses to nal­
trexone administration might be useful for identifying
people who are more sensitive to food reward.165 Research
in patients with obesity and binge eating disorder, however,
showed no significant differences in binge-eating fre­
quency between groups receiving placebo or the opioid
antagonist samidorphan (ALKS 33).166
Genetic studies focused on the OPRM1 gene, which
encodes the μ‑opioid receptor, have largely been con­
cerned with the 118A>G single-nucleotide polymorphism,
which has been associated with heightened reward sensi­
tivity and addiction in some, although not all, studies.167
No correlations have been shown between this gene and
BMI,120,126 but an association has been reported between
OPRM1 and fat intake168 and preference for foods high
in sugar and/or fat in individuals with homozygous GG
alleles.167 Davis and colleagues169 found that a greater per­
centage of participants with binge eating disorder had the
OPRM1*G allele, but not the TaqI DRD2*A1 allele, than
participants with obesity. Furthermore, participants with
obesity were more likely to have the TaqI DRD2*A1 allele
but not the OPRM1*G allele. The authors suggest that
these findings indicate an increased hedonic drive to eat
in binge eaters, and, consistent with findings described
above, decreased availability of dopamine D2 receptors
in individuals with obesity. Finally, a trend towards an
interaction between the presence of the OPRM1*G allele
and the TaqI DRD2*A1 allele in participants with obesity
has been reported.126
REVIEWS

Box 1 | Symptoms assessed by the Yale Food Addiction Scale using Goodman’s Addictive Disorder Criteria175 and an
adapted form of the substance-dependence criteria con­
■■ Substance taken in larger amounts and for a longer period than intended
■■ Persistent desire or repeated unsuccessful attempts to quit
tained in the Diagnostic and Statistical Manual of Mental
■■ Substantial time and/or activity to obtain, use and/or recover Disorders 4th edition, in which they replaced the term
■■ Important social, occupational or recreational activities given up or reduced ‘substance’ with ‘binge eating’. They found that 92.4% of
■■ Use continues despite knowledge of adverse consequences (for example, participants met the Diagnostic and Statistical Manual
failure to fulfil role obligation or used when physically hazardous) of Mental Disorders criteria and 40.5% met the criteria
■■ Tolerance (marked increase in amount taken or marked decrease in effect) put forth by Goodman. A later qualitative study found
■■ Characteristic withdrawal symptoms or substance taken to relieve withdrawal that every woman with obesity interviewed who had a
■■ Use causes severe clinical impairment
binge eating disorder met the modified Diagnostic and
Statistical Manual of Mental Disorders 5th edition criteria,
as did almost half of the women with obesity but without
Table 1 | Studies on the prevalence of food addiction*
binge eating disorder.176 Further support for the concept
Study Number of Study sample Food of food addiction comes from a study of addiction-­like
participants addiction (%)
eating behaviour among candidates for bariatric surgery,
Gearhardt et al. (2012)6 81 Adults with obesity and BED 56.8 in which a positive correlation was found between
Clark & Saules 67 Postbariatric surgery adult 53.7§ addictive personality scores on the Eysenck Personality
(2013)193‡ patients Questionnaire Addiction Scale and over­e ating. 177
Bégin et al. (2012)189 23 Overweight women and 47.8 Furthermore, the addictive personality scores for partici­
women with obesity pants with binge eating disorder were similar to those
Meule et al. (2012)194 96 Adults with obesity who were 41.7 reported for individuals with substance addictions.
bariatric surgery candidates The Yale Food Addiction Scale (Box 1) was intro­
Gearhardt et al. (2013)187 96 Adults with obesity and BED 41.5 duced in 2009 to assess food addiction symptoms in
Gearhardt et al. (2011)180 39 Healthy young women 38.4§ clinical samples and is based on the criteria for substance
Davis et al. (2011) 7
72 Adults with obesity 25
dependence in Diagnostic and Statistical Manual of
Mental Disorders 4th edition and other behavioural addic­
Murphy et al. (2014)186 233 Undergraduate students 24
tion assessment tools. This scale offers two options for
Burmeister et al. 57 Overweight adults and adults 19.6§ scoring. One is a dichotomous “yes/no” food addiction
(2013)179 with obesity
diagnosis, which is made when an individual meets three
Davis et al. (2013)178 120 Men and women 17.5 or more food addiction criteria as well as reports clini­
Eichen et al. (2013)182 178 Overweight adults and adults 15.2 cally significant impairment. The second is a symptom
with obesity count. Several studies have used this scale to assess
Lent et al. (2013)191 154 Adults seeking weight-loss 15.2 addiction-like eating behaviour in various groups. Food
treatment addiction diagnoses have been made most frequently
Gearhardt et al. (2009)195 233 Undergraduate students 11.4 in study groups comprising predominantly individuals
Meule et al. (2012)196 752 Young adults (predominantely 8.8 with obesity (with or without binge eating disorder) and
female students) overweight individuals (Table 1). No significant differ­
Meule & Kubler (2012)188 616 Young adults (predominantely 8.5 ences, however, have been found in BMI between groups
female students) classified as addicted and not addicted to food,7,178–182
Mason et al. (2013)184 57,321 Adult women 8.2 despite several studies having reported increasing food
Gearhardt et al. (2013) 183
75 Children and adolescents 7.2 addiction scores with increasing body weight.63,183–186 In
an effort to recon­cile these conflicting findings, a cubic
Flint et al. (2014)197 134,175 Adult women (Nurses’ Health 5.8
Studies I and II participants) rather than a linear association has been suggested. That
is, food addiction symptoms may differ between normal
Pedram et al. (2013)63 652 Adult men and women 5.4
and overweight categories, as well as between individu­
Meule et al. (2012)185 50 Normal-weight female 4 als with moderate and severe obesity, but not between
undergraduate students
underweight and normal-weight groups nor over­
*Classified with the Yale Food Addiction Scale. ‡Retrospective data. §Calculated on the basis of the
less-stringent diagnosis option of a score of ≥3. Abbreviation: BED, binge-eating disorder. weight and obese groups.181 Additionally, some studies
compared BMI by diagnosis (food addicted versus not
addicted) rather than reporting correlations between
Clinical evidence of addiction to food Yale Food Addiction Scale scores and BMI.
Assessment of food addiction in humans
Expanding on previously discussed findings, in this Implications of food addiction
section we present clinical evidence suggestive of food Studies in which the Yale Food Addiction Scale was used
addiction in humans. While research in this area has have revealed several noteworthy findings regarding the
expanded considerably in the past decade, the concept of psychological correlates of food addiction, the most
food addiction is not new and debates on this topic have common being binge eating, emotionally driven eating
been ongoing for several decades.170–173 In 2007, Cassin and food cravings.6,7,178–180,187–189 Additionally, various
and von Ranson 174 assessed addiction-like relation­ studies have noted evidence of increased impulsivity in
ships to food in women with binge eating disorder participants with food addiction diagnoses or high Yale

8  |  ADVANCE ONLINE PUBLICATION www.nature.com/nrendo

© 2014 Macmillan Publishers Limited. All rights reserved
 REVIEWS

Food Addiction Scale scores.6,7,185,189 For instance, in a
study of women with and without food addiction who
were overweight or had obesity and who were seeking
treatment for compulsive overeating and weight manage­
ment, as well as a group of women with substance use
disorders, greater impulsivity was reported in those with
food addiction than in those without.189 Furthermore,
impulsivity scores did not differ significantly between
women with food addiction and those with a substance
use disorder. Another study found an indirect relation­
ship between impulsivity and BMI by way of associations
with Yale Food Addiction Scale scores.186 Additionally,
several studies using the Yale Food Addiction Scale have
shown associations between food addiction and depres­
sion or negative affect,6,7,179,182,187 but these findings have
not been universally supported.183,189
Differential patterns of neural activation, defined
according to Yale Food Addiction Scale scores, have been
observed during the anticipation of and receipt of highly
palatable foods.180 More specifically, activation of brain
regions associated with motivation to eat and craving
increases with increasing Yale Food Addiction Scale
scores when highly palatable food is anticipated, and acti­
vation in the left lateral orbitofrontal cortex, which has
been associated with inhibition, decreases during con­
sumption. Additionally, compared with participants with
less than two food addiction symptoms of the Yale Food
Addiction Scale, those with two or more food addiction
symptoms showed faster reaction times when shown pic­
tures of highly palatable food items than when shown
neutral cues.185 Together, these findings suggest that food
addiction is associated with a heightened response when
anticipating a food reward and encounter­ing food cues.
As noted by Berridge and colleagues,190 these individuals
might be more likely to want food, but further investi­
gation would be needed to determine whether food
addiction characteristics are associ­ated with increased
or decreased liking of food when consumed. In terms of
dopaminergic function, increased dopamine signalling
has been reported among indivi­duals with food addic­
tion diagnoses compared with those without, which,
the authors note, provides preliminary support for a
potential predisposition to excessive food intake and
a­ddictive‑like behaviour towards food.178
These findings beg the important question of whether
the food addiction construct is clinically relevant. In an
attempt to answer this question, studies have assessed
how Yale Food Addiction Scale scores correspond
to differential outcomes in weight loss studies. High
Yale Food Addiction Scale scores were associated with
reduced weight loss in one study,179 but when binge
eating was also entered into the regression analysis,
scores were no longer significantly associated with
weight loss. Another study found no significant relation­
ship between Yale Food Addiction Scale scores and
variance in weight change.191 Research has also begun
to consider how food addiction might relate to factors
beyond weight loss. In one study, history of severe physi­
cal and sexual abuse in childhood and adolescence was
associated with roughly 90% increase in risk of food
addiction in adult women.184 Although food addiction
remains a controversial topic in the general population
and the scientific community,103,107,192 research focused on
developing and assessing treatments designed to target
aspects of food addiction might elucidate the clinical
utility of this construct.
Conclusions
Hormones that influence feeding behaviour, namely
leptin, ghrelin and insulin, also seem to interact with
or modulate neural systems implicated in reward func­
tion. These findings expand and deepen understanding
of the factors involved in overeating and certain cases of
obesity. Additionally, evidence dem­onstrates that over­
eating, particularly of highly palatable foods, can affect
the dopaminergic and opioidergic brain systems, which,
in certain cases, seems to lead to the development of
addiction-like behaviour. Although substantial work
has been done in this area in the past few years, further
research is needed to clarify the precise inter­actions
between hormones, brain reward mechanisms and
o­vereating, as well as obesity.
Review criteria
A search for original-research and review articles
published between 1980 and 2014 and focusing on food
reward was performed in PubMed. The search terms
used were “obesity”, “overeating”, “reward”, “neural”,
“insulin”, “leptin”, “ghrelin”, “dopamine”, “opioids”,
“palatable”, “food” and “addiction”, alone and in
combination. All articles identified were English-language
(with one German-language exception), full-text papers.
We also searched the reference lists of identified articles
for further relevant papers. Finally, we used our up-to-date
collection of articles that included the Yale Food Addiction
Scale in their methods and analyses.

1. Kobeissy, F. H., Jeung, J. A., Warren, M. W.,
Geier, J. E. & Gold, M. S. Changes in leptin,
ghrelin, growth hormone and neuropeptide‑Y
after an acute model of MDMA and
methamphetamine exposure in rats. Addict. Biol.
13, 15–25 (2008).
2. Gold, M. S. From bedside to bench and back
again: a 30-year saga. Physiol. Behav. 104,
157–161 (2011).
3. Avena, N. M., Rada, P. & Hoebel, B. G.
Evidence for sugar addiction: behavioral and
neurochemical effects of intermittent, excessive
sugar intake. Neurosci. Biobehav. Rev. 32, 20–39
(2008).
4. Johnson, P. M. & Kenny, P. J. Dopamine D2
receptors in addiction-like reward
dysfunction and compulsive eating in
obese rats. Nat. Neurosci. 13, 635–641
(2010).
5. Oswald, K. D., Murdaugh, D. L., King, V. L.
& Boggiano, M. M. Motivation for palatable
food despite consequences in an animal
model of binge eating. Int. J. Eat. Disord. 44,
203–211 (2011).
6. Gearhardt, A. N. et al. An examination of the
food addiction construct in obese patients
with binge eating disorder. Int. J. Eat. Disord.
45, 657–663 (2012).
7. Davis, C. et al. Evidence that ‘food addiction’
is a valid phenotype of obesity. Appetite 57,
711–717 (2011).
8. Edge, P. J. & Gold, M. S. Drug withdrawal and
hyperphagia: lessons from tobacco and other
drugs. Curr. Pharm. Des. 17, 1173–1179 (2011).
9. Keen-Rhinehart, E., Ondek, K. & Schneider, J. E.
Neuroendocrine regulation of appetitive
ingestive behavior. Front. Neurosci. 7, 213
(2013).
10. Suzuki, K., Simpson, K. A., Minnion, J. S.,
Shillito, J. C. & Bloom, S. R. The role of gut
hormones and the hypothalamus in appetite
regulation. Endocr. J. 57, 359–372 (2010).

NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  9

© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
11. Sam, A. H., Troke, R. C., Tan, T. M. &
Bewick, G. A. The role of the gut/brain axis in
modulating food intake. Neuropharmacology 63,
46–56 (2012).
12. Rui, L. Brain regulation of energy balance and
body weight. Rev. Endocr. Metab. Disord. 14,
387–407 (2013).
13. Scott, R., Tan, T. & Bloom, S. Gut hormones and
obesity: physiology and therapies. Vitam. Horm.
91, 143–194 (2013).
14. Fulton, S. et al. Leptin regulation of the
mesoaccumbens dopamine pathway. Neuron 51,
811–822 (2006).
15. Hommel, J. D. et al. Leptin receptor signaling in
midbrain dopamine neurons regulates feeding.
Neuron 51, 801–810 (2006).
16. Bouret, S. G., Draper, S. J. & Simerly, R. B.
Trophic action of leptin on hypothalamic neurons
that regulate feeding. Science 304, 108–110
(2004).
17. Bruijnzeel, A. W., Corrie, L. W., Rogers, J. A. &
Yamada, H. Effects of insulin and leptin in the
ventral tegmental area and arcuate hypothalamic
nucleus on food intake and brain reward function
in female rats. Behav. Brain Res. 219, 254–264
(2011).
18. Morton, G. J., Blevins, J. E., Kim, F., Matsen, M.
& Figlewicz, D. P. The action of leptin in the
ventral tegmental area to decrease food intake
is dependent on Jak‑2 signaling. Am. J. Physiol.
Endocrinol. Metab. 297, E202–E210 (2009).
19. Leinninger, G. M. et al. Leptin acts via leptin
receptor-expressing lateral hypothalamic
neurons to modulate the mesolimbic dopamine
system and suppress feeding. Cell Metab. 10,
89–98 (2009).
20. Kumer, S. C. & Vrana, K. E. Intricate regulation
of tyrosine hydroxylase activity and gene
expression. J. Neurochem. 67, 443–462
(1996).
21. Leinninger, G. M. et al. Leptin action via
neurotensin neurons controls orexin, the
mesolimbic dopamine system and energy
balance. Cell Metab. 14, 313–323 (2011).
22. Opland, D. et al. Loss of neurotensin receptor‑1
disrupts the control of the mesolimbic dopamine
system by leptin and promotes hedonic feeding
and obesity. Mol. Metab. 2, 423–434 (2013).
23. Leshan, R. L. et al. Ventral tegmental area
leptin receptor neurons specifically project to
and regulate cocaine- and amphetamine-
regulated transcript neurons of the extended
central amygdala. J. Neurosci. 30, 5713–5723
(2010).
24. Thompson, J. L. & Borgland, S. L. Presynaptic
leptin action suppresses excitatory synaptic
transmission onto ventral tegmental area
dopamine neurons. Biol. Psychiatry 73, 860–868
(2013).
25. Bruijnzeel, A. W., Qi, X. & Corrie, L. W. Anorexic
effects of intra-VTA leptin are similar in low-fat
and high‑fat‑fed rats but attenuated in a
subgroup of high‑fat‑fed obese rats. Pharmacol.
Biochem. Behav. 103, 573–581 (2013).
26. Scarpace, P. J. et al. Leptin overexpression in
VTA trans-activates the hypothalamus whereas
prolonged leptin action in either region cross-
desensitizes. Neuropharmacology 65, 90–100
(2013).
27. Matheny, M., Shapiro, A., Tumer, N. &
Scarpace, P. J. Region-specific diet-induced
and leptin-induced cellular leptin resistance
includes the ventral tegmental area in rats.
Neuropharmacology 60, 480–487 (2011).
28. Rothemund, Y. et al. Differential activation of the
dorsal striatum by high-calorie visual food stimuli
in obese individuals. Neuroimage 37, 410–421
(2007).
10  |  ADVANCE ONLINE PUBLICATION
29. Grosshans, M. et al. Association of leptin with
food cue-induced activation in human reward
pathways. Arch. Gen. Psychiatry 69, 529–537
(2012).
30. Rosenbaum, M., Sy, M., Pavlovich, K.,
Leibel, R. L. & Hirsch, J. Leptin reverses weight
loss-induced changes in regional neural activity
responses to visual food stimuli. J. Clin. Invest.
118, 2583–2591 (2008).
31. Hinkle, W., Cordell, M., Leibel, R.,
Rosenbaum, M. & Hirsch, J. Effects of reduced
weight maintenance and leptin repletion on
functional connectivity of the hypothalamus in
obese humans. PLoS ONE 8, e59114 (2013).
32. Geliebter, A., Hashim, S. A. & Gluck, M. E.
Appetite-related gut peptides, ghrelin, PYY,
and GLP‑1 in obese women with and without
binge eating disorder (BED). Physiol. Behav. 94,
696–699 (2008).
33. Geliebter, A., Yahav, E. K., Gluck, M. E. &
Hashim, S. A. Gastric capacity, test meal intake,
and appetitive hormones in binge eating
disorder. Physiol. Behav. 81, 735–740 (2004).
34. Geliebter, A., Gluck, M. E. & Hashim, S. A.
Plasma ghrelin concentrations are lower in binge-
eating disorder. J. Nutr. 135, 1326–1330 (2005).
35. Monteleone, P. et al. Circulating ghrelin is
decreased in non-obese and obese women with
binge eating disorder as well as in obese non-
binge eating women, but not in patients with
bulimia nervosa. Psychoneuroendocrinology 30,
243–250 (2005).
36. Abizaid, A. et al. Ghrelin modulates the activity
and synaptic input organization of midbrain
dopamine neurons while promoting appetite.
J. Clin. Invest. 116, 3229–3239 (2006).
37. Lindqvist, A., de la Cour, C. D., Stegmark, A.,
Hakanson, R. & Erlanson-Albertsson, C.
Overeating of palatable food is associated
with blunted leptin and ghrelin responses.
Regul. Pept. 130, 123–132 (2005).
38. Perello, M. et al. Ghrelin increases the rewarding
value of high-fat diet in an orexin-dependent
manner. Biol. Psychiatry 67, 880–886 (2010).
39. Skibicka, K. P., Hansson, C., Alvarez-Crespo, M.,
Friberg, P. A. & Dickson, S. L. Ghrelin directly
targets the ventral tegmental area to increase
food motivation. Neuroscience 180, 129–137
(2011).
40. Egecioglu, E. et al. Ghrelin increases intake
of rewarding food in rodents. Addict. Biol. 15,
304–311 (2010).
41. Jerlhag, E., Janson, A. C., Waters, S. &
Engel, J. A. Concomitant release of ventral
tegmental acetylcholine and accumbal
dopamine by ghrelin in rats. PLoS ONE 7,
e49557 (2012).
42. Skibicka, K. P. et al. Divergent circuitry underlying
food reward and intake effects of ghrelin:
dopaminergic VTA-accumbens projection
mediates ghrelin’s effect on food reward but not
food intake. Neuropharmacology 73, 274–283
(2013).
43. Skibicka, K. P., Hansson, C., Egecioglu, E. &
Dickson, S. L. Role of ghrelin in food reward:
impact of ghrelin on sucrose self-administration
and mesolimbic dopamine and acetylcholine
receptor gene expression. Addict. Biol. 17,
95–107 (2012).
44. Skibicka, K. P., Shirazi, R. H., Hansson, C.
& Dickson, S. L. Ghrelin interacts with
neuropeptide Y Y1 and opioid receptors to
increase food reward. Endocrinology 153,
1194–1205 (2012).
45. Kawahara, Y. et al. Food reward-sensitive
interaction of ghrelin and opioid receptor
pathways in mesolimbic dopamine system.
Neuropharmacology 67, 395–402 (2013).
© 2014 Macmillan Publishers Limited. All rights reserved
46. Monteleone, P. et al. Gastroenteric hormone
responses to hedonic eating in healthy humans.
Psychoneuroendocrinology 38, 1435–1441
(2013).
47. Monteleone, P. et al. Hedonic eating is
associated with increased peripheral levels
of ghrelin and the endocannabinoid
2‑arachidonoyl‑glycerol in healthy humans:
a pilot study. J. Clin. Endocrinol. Metab.
97, E917–E924 (2012).
48. Banks, W. A., Owen, J. B. & Erickson, M. A.
Insulin in the brain: there and back again.
Pharmacol. Ther. 136, 82–93 (2012).
49. Figlewicz, D. P., Evans, S. B., Murphy, J., Hoen, M.
& Baskin, D. G. Expression of receptors for
insulin and leptin in the ventral tegmental area/
substantia nigra (VTA/SN) of the rat. Brain Res.
964, 107–115 (2003).
50. Labouèbe, G. et al. Insulin induces long-term
depression of ventral tegmental area dopamine
neurons via endocannabinoids. Nat. Neurosci.
16, 300–308 (2013).
51. Figlewicz, D. P., Bennett, J. L., Aliakbari, S.,
Zavosh, A. & Sipols, A. J. Insulin acts at different
CNS sites to decrease acute sucrose intake
and sucrose self-administration in rats. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 295,
R388–R394 (2008).
52. Mebel, D. M., Wong, J. C., Dong, Y. J. &
Borgland, S. L. Insulin in the ventral tegmental
area reduces hedonic feeding and suppresses
dopamine concentration via increased reuptake.
Eur. J. Neurosci. 36, 2336–2346 (2012).
53. Könner, A. C. et al. Role for insulin signaling in
catecholaminergic neurons in control of energy
homeostasis. Cell Metab. 13, 720–728 (2011).
54. Jauch-Chara, K. et al. Intranasal insulin
suppresses food intake via enhancement of
brain energy levels in humans. Diabetes 61,
2261–2268 (2012).
55. Hallschmid, M., Higgs, S., Thienel, M., Ott, V.
& Lehnert, H. Postprandial administration of
intranasal insulin intensifies satiety and reduces
intake of palatable snacks in women. Diabetes
61, 782–789 (2012).
56. Kroemer, N. B. et al. (Still) longing for food:
insulin reactivity modulates response to food
pictures. Hum. Brain Mapp. 34, 2367–2380
(2013).
57. Stice, E., Figlewicz, D. P., Gosnell, B. A.,
Levine, A. S. & Pratt, W. E. The contribution
of brain reward circuits to the obesity epidemic.
Neurosci. Biobehav. Rev. 37, 2047–2058 (2013).
58. Kenny, P. J. Reward mechanisms in obesity:
new insights and future directions. Neuron 69,
664–679 (2011).
59. Volkow, N. D. & Wise, R. A. How can drug
addiction help us understand obesity?
Nat. Neurosci. 8, 555–560 (2005).
60. [No authors listed] The neural basis of feeding
and reward. Festschrift dedicated to Dr Bart
Hoebel. January 14, 2011. Princeton, New
Jersey, USA. Physiol. Behav. 104, 1–177 (2011).
61. Blumenthal, D. M. & Gold, M. S. Neurobiology of
food addiction. Curr. Opin. Clin. Nutr. Metab. Care
13, 359–365 (2010).
62. DiLeone, R. J., Taylor, J. R. & Picciotto, M. R.
The drive to eat: comparisons and distinctions
between mechanisms of food reward and drug
addiction. Nat. Neurosci. 15, 1330–1335
(2012).
63. Pedram, P. et al. Food addiction: its prevalence
and significant association with obesity in the
general population. PLoS ONE 8, e74832
(2013).
64. Volkow, N. D., Wang, G. J., Tomasi, D. &
Baler, R. D. Obesity and addiction: neurobiological
overlaps. Obes. Rev. 14, 2–18 (2013).
www.nature.com/nrendo

65. Ochner, C. N., Barrios, D. M., Lee, C. D. &
Pi‑Sunyer, F. X. Biological mechanisms that
promote weight regain following weight loss in
obese humans. Physiol. Behav. 120, 106–113
(2013).
66. Ikemoto, S. & Panksepp, J. The role of nucleus
accumbens dopamine in motivated behavior:
a unifying interpretation with special reference
to reward-seeking. Brain Res. Brain Res. Rev. 31,
6–41 (1999).
67. Hajnal, A. & Norgren, R. Accumbens dopamine
mechanisms in sucrose intake. Brain Res. 904,
76–84 (2001).
68. Bassareo, V. & Di Chiara, G. Differential
responsiveness of dopamine transmission to
food-stimuli in nucleus accumbens shell/core
compartments. Neuroscience 89, 637–641
(1999).
69. Hernández, L., Paredes, D. & Rada, P. Feeding
behavior as seen through the prism of brain
microdialysis. Physiol. Behav. 104, 47–56
(2011).
70. Beeler, J. A., Frazier, C. R. & Zhuang, X. Putting
desire on a budget: dopamine and energy
expenditure, reconciling reward and resources.
Front. Integr. Neurosci. 6, 49 (2012).
71. Geiger, B. M. et al. Evidence for defective
mesolimbic dopamine exocytosis in obesity-
prone rats. FASEB J. 22, 2740–2746 (2008).
72. Geiger, B. M. et al. Deficits of mesolimbic
dopamine neurotransmission in rat dietary
obesity. Neuroscience 159, 1193–1199 (2009).
73. Rada, P., Bocarsly, M. E., Barson, J. R.,
Hoebel, B. G. & Leibowitz, S. F. Reduced
accumbens dopamine in Sprague–Dawley rats
prone to overeating a fat-rich diet. Physiol. Behav.
101, 394–400 (2010).
74. Hansen, H. H., Jensen, M. M., Overgaard, A.,
Weikop, P. & Mikkelsen, J. D. Tesofensine
induces appetite suppression and weight loss
with reversal of low forebrain dopamine levels in
the diet-induced obese rat. Pharmacol. Biochem.
Behav. 110, 265–271 (2013).
75. Alsiö, J. et al. Dopamine D1 receptor gene
expression decreases in the nucleus
accumbens upon long-term exposure to
palatable food and differs depending on diet-
induced obesity phenotype in rats. Neuroscience
171, 779–787 (2010).
76. Alsiö, J. et al. Exposure to a high-fat high-sugar
diet causes strong up-regulation of
proopiomelanocortin and differentially affects
dopamine D1 and D2 receptor gene expression
in the brainstem of rats. Neurosci. Lett. 559,
18–23 (2014).
77. van de Giessen, E., la Fleur, S. E., de Bruin, K.,
van den Brink, W. & Booij, J. Free-choice and no-
choice high-fat diets affect striatal dopamine D2/3
receptor availability, caloric intake, and adiposity.
Obesity (Silver Spring) 20, 1738–1740 (2012).
78. van de Giessen, E. et al. High fat/carbohydrate
ratio but not total energy intake induces lower
striatal dopamine D2/3 receptor availability in
diet-induced obesity. Int. J. Obes. (Lond.) 37,
754–757 (2013).
79. Speed, N. et al. Impaired striatal Akt signaling
disrupts dopamine homeostasis and increases
feeding. PLoS ONE 6, e25169 (2011).
80. Fetissov, S. O., Meguid, M. M., Sato, T. &
Zhang, L. H. Expression of dopaminergic
receptors in the hypothalamus of lean and
obese Zucker rats and food intake. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 283,
R905–R910 (2002).
81. Trifilieff, P. & Martinez, D. Imaging addiction:
D2 receptors and dopamine signaling in the
striatum as biomarkers for impulsivity.
Neuropharmacology 76, 498–509 (2014).
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  11
82. Marco, A., Schroeder, M. & Weller, A. Feeding
and reward: ontogenetic changes in an animal
model of obesity. Neuropharmacology 62,
2447–2454 (2012).
83. Kim, K. S. et al. Enhanced hypothalamic leptin
signaling in mice lacking dopamine D2 receptors.
J. Biol. Chem. 285, 8905–8917 (2010).
84. Corwin, R. L. & Wojnicki, F. H. Baclofen, raclopride,
and naltrexone differentially affect intake of fat
and sucrose under limited access conditions.
Behav. Pharmacol. 20, 537–548 (2009).
85. Pritchett, C. E. & Hajnal, A. Obesogenic diets
may differentially alter dopamine control
of sucrose and fructose intake in rats.
Physiol. Behav. 104, 111–116 (2011).
86. Wong, K. J., Wojnicki, F. H. & Corwin, R. L.
Baclofen, raclopride, and naltrexone differentially
affect intake of fat/sucrose mixtures under
limited access conditions. Pharmacol. Biochem.
Behav. 92, 528–536 (2009).
87. Koerber, J., Goodman, D., Barnes, J. L.
& Grimm, J. W. The dopamine D2 antagonist
eticlopride accelerates extinction and delays
reacquisition of food self-administration in rats.
Behav. Pharmacol. 24, 633–639 (2013).
88. van de Giessen, E., de Bruin, K., la Fleur, S. E.,
van den Brink, W. & Booij, J. Triple monoamine
inhibitor tesofensine decreases food intake,
body weight, and striatal dopamine D2/D3
receptor availability in diet-induced obese rats.
Eur. Neuropsychopharmacol. 22, 290–299
(2012).
89. Avena, N. M., Bocarsly, M. E., Rada, P., Kim, A.
& Hoebel, B. G. After daily bingeing on a sucrose
solution, food deprivation induces anxiety and
accumbens dopamine/acetylcholine imbalance.
Physiol. Behav. 94, 309–315 (2008).
90. Avena, N. M., Rada, P. & Hoebel, B. G.
Underweight rats have enhanced dopamine
release and blunted acetylcholine response
in the nucleus accumbens while bingeing on
sucrose. Neuroscience 156, 865–871 (2008).
91. Baik, J. H. Dopamine signaling in reward-related
behaviors. Front. Neural Circuits 7, 152 (2013).
92. Pickering, C., Alsiö, J., Hulting, A. L. &
Schiöth, H. B. Withdrawal from free-choice high-
fat high-sugar diet induces craving only in
obesity-prone animals. Psychopharmacology
(Berl.) 204, 431–443 (2009).
93. de Jong, J. W., Meijboom, K. E.,
Vanderschuren, L. J. & Adan, R. A. Low control
over palatable food intake in rats is associated
with habitual behavior and relapse vulnerability:
individual differences. PLoS ONE 8, e74645
(2013).
94. Colantuoni, C. et al. Excessive sugar intake
alters binding to dopamine and μ-opioid
receptors in the brain. Neuroreport 12,
3549–3452 (2001).
95. Bello, N. T., Lucas, L. R. & Hajnal, A. Repeated
sucrose access influences dopamine D2
receptor density in the striatum. Neuroreport 13,
1575–1578 (2002).
96. Hajnal, A. & Norgren, R. Repeated access
to sucrose augments dopamine turnover in
the nucleus accumbens. Neuroreport 13,
2213–2216 (2002).
97. Bello, N. T., Sweigart, K. L., Lakoski, J. M.,
Norgren, R. & Hajnal, A. Restricted feeding
with scheduled sucrose access results in an
upregulation of the rat dopamine transporter.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 284,
R1260–R1268 (2003).
98. Chandler-Laney, P. C. et al. A history of caloric
restriction induces neurochemical and
behavioral changes in rats consistent with
models of depression. Pharmacol. Biochem.
Behav. 87, 104–114 (2007).
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
99. Davis, J. F. et al. Exposure to elevated levels of
dietary fat attenuates psychostimulant reward
and mesolimbic dopamine turnover in the rat.
Behav. Neurosci. 122, 1257–1263 (2008).
100. Rada, P., Avena, N. M. & Hoebel, B. G. Daily
bingeing on sugar repeatedly releases dopamine
in the accumbens shell. Neuroscience 134,
737–744 (2005).
101. Avena, N. M., Rada, P., Moise, N. & Hoebel, B. G.
Sucrose sham feeding on a binge schedule
releases accumbens dopamine repeatedly and
eliminates the acetylcholine satiety response.
Neuroscience 139, 813–820 (2006).
102. Liang, N. C., Hajnal, A. & Norgren, R. Sham
feeding corn oil increases accumbens dopamine
in the rat. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 291, R1236–R1239 (2006).
103. Avena, N. & Hoebel, B. in Food and Addiction:
A Comprehensive Handbook Ch. 31
(eds Brownell, K. & Gold, M.) 206–213
(Oxford University Press, 2012).
104. Colantuoni, C. et al. Evidence that intermittent,
excessive sugar intake causes endogenous
opioid dependence. Obes. Res. 10, 478–488
(2002).
105. Avena, N. M., Long, K. A. & Hoebel, B. G.
Sugar‑dependent rats show enhanced
responding for sugar after abstinence: evidence
of a sugar deprivation effect. Physiol. Behav. 84,
359–362 (2005).
106. Wilson, G. T. Eating disorders, obesity and
addiction. Eur. Eat. Disord. Rev. 18, 341–351
(2010).
107. Ziauddeen, H., Farooqi, I. S. & Fletcher, P. C.
Obesity and the brain: how convincing is the
addiction model? Nat. Rev. Neurosci. 13,
279–286 (2012).
108. Wang, G. J. et al. Brain dopamine and obesity.
Lancet 357, 354–357 (2001).
109. Haltia, L. T. et al. Effects of intravenous glucose
on dopaminergic function in the human brain
in vivo. Synapse 61, 748–756 (2007).
110. Volkow, N. D. et al. Low dopamine striatal D2
receptors are associated with prefrontal
metabolism in obese subjects: possible
contributing factors. Neuroimage 42,
1537–1543 (2008).
111. Dunn, J. P. et al. Relationship of dopamine
type 2 receptor binding potential with fasting
neuroendocrine hormones and insulin sensitivity
in human obesity. Diabetes Care 35, 1105–1111
(2012).
112. Volkow, N. D. et al. Brain dopamine is associated
with eating behaviors in humans. Int. J. Eat.
Disord. 33, 136–142 (2003).
113. Wang, G. J. et al. Enhanced striatal dopamine
release during food stimulation in binge eating
disorder. Obesity (Silver Spring) 19, 1601–1608
(2011).
114. Broft, A. et al. Striatal dopamine in bulimia
nervosa: a PET imaging study. Int. J. Eat. Disord.
45, 648–656 (2012).
115. Wilcox, C. E., Braskie, M. N., Kluth, J. T. &
Jagust, W. J. Overeating behavior and striatal
dopamine with 6‑[F]‑fluoro‑l‑m‑tyrosine PET.
J. Obes. http://dx.doi.org/10.1155/2010/
909348 (2010).
116. Lee, B. et al. Striatal dopamine D2/D3 receptor
availability is reduced in methamphetamine
dependence and is linked to impulsivity.
J. Neurosci. 29, 14734–14740 (2009).
117. Buckholtz, J. W. et al. Dopaminergic network
differences in human impulsivity. Science 329,
532 (2010).
118. Eisenberg, D. T. et al. Examining impulsivity as
an endophenotype using a behavioral approach:
a DRD2 TaqI A and DRD4 48‑bp VNTR association
study. Behav. Brain Funct. 3, 2 (2007).
REVIEWS
119. Noble, E. P. D2 dopamine receptor gene in
psychiatric and neurologic disorders and its
phenotypes. Am. J. Med. Genet. B Neuropsychiatr.
Genet. 116B, 103–125 (2003).
120. Hardman, C. A., Rogers, P. J., Timpson, N. J.
& Munafo, M. R. Lack of association between
DRD2 and OPRM1 genotypes and adiposity.
Int. J. Obes. (Lond.) 38, 730–736 (2014).
121. Epstein, L. H. et al. Food reinforcement, the
dopamine D2 receptor genotype, and energy
intake in obese and nonobese humans.
Behav. Neurosci. 121, 877–886 (2007).
122. Winkler, J. K. et al. TaqIA polymorphism in
dopamine D2 receptor gene complicates weight
maintenance in younger obese patients.
Nutrition 28, 996–1001 (2012).
123. Stice, E., Spoor, S., Bohon, C. & Small, D. M.
Relation between obesity and blunted striatal
response to food is moderated by TaqIA A1
allele. Science 322, 449–452 (2008).
124. Stice, E., Yokum, S., Bohon, C., Marti, N.
& Smolen, A. Reward circuitry responsivity to
food predicts future increases in body mass:
moderating effects of DRD2 and DRD4.
Neuroimage 50, 1618–1625 (2010).
125. Davis, C. et al. Binge eating disorder and the
dopamine D2 receptor: genotypes and sub-
phenotypes. Prog. Neuropsychopharmacol. Biol.
Psychiatry 38, 328–335 (2012).
126. Carpenter, C. L., Wong, A. M., Li, Z., Noble, E. P.
& Heber, D. Association of dopamine D2 receptor
and leptin receptor genes with clinically severe
obesity. Obesity (Silver Spring) 21, E467–E473
(2013).
127. Chen, A. L. et al. Correlation of the Taq1
dopamine D2 receptor gene and percent body
fat in obese and screened control subjects:
a preliminary report. Food Funct. 3, 40–48
(2012).
128. Comings, D. E., Gade, R., MacMurray, J. P.,
Muhleman, D. & Peters, W. R. Genetic variants
of the human obesity (OB) gene: association
with body mass index in young women,
psychiatric symptoms, and interaction with
the dopamine D2 receptor (DRD2) gene.
Mol. Psychiatry 1, 325–335 (1996).
129. Jenkinson, C. P. et al. Association of
dopamine D2 receptor polymorphisms
Ser311Cys and TaqIA with obesity or type 2
diabetes mellitus in Pima Indians. Int. J. Obes.
Relat. Metab. Disord. 24, 1233–1238 (2000).
130. Roth, C. L., Hinney, A., Schur, E. A., Elfers, C. T.
& Reinehr, T. Association analyses for dopamine
receptor gene polymorphisms and weight status
in a longitudinal analysis in obese children
before and after lifestyle intervention.
BMC Pediatr. 13, 197 (2013).
131. Ariza, M. et al. Dopamine genes (DRD2/ANKK1-
TaqA1 and DRD4–7R) and executive function:
their interaction with obesity. PLoS ONE 7,
e41482 (2012).
132. Snyder, S. H. & Pasternak, G. W. Historical
review: opioid receptors. Trends Pharmacol. Sci.
24, 198–205 (2003).
133. Blasio, A., Steardo, L., Sabino, V. & Cottone, P.
Opioid system in the medial prefrontal cortex
mediates binge-like eating. Addict. Biol. http://
dx.doi.org/10.1111/adb.12033 (2013).
134. Chang, G. Q., Karatayev, O., Barson, J. R.,
Chang, S. Y. & Leibowitz, S. F. Increased
enkephalin in brain of rats prone to
overconsuming a fat-rich diet. Physiol. Behav.
101, 360–369 (2010).
135. Cooper, S. J., Jackson, A. & Kirkham, T. C.
Endorphins and food intake: kappa opioid
receptor agonists and hyperphagia.
Pharmacol. Biochem. Behav. 23, 889–901
(1985).
12  |  ADVANCE ONLINE PUBLICATION
136. Kelley, A. E. et al. Opioid modulation of taste
hedonics within the ventral striatum.
Physiol. Behav. 76, 365–377 (2002).
137. Kelley, A. E., Will, M. J., Steininger, T. L.,
Zhang, M. & Haber, S. N. Restricted daily
consumption of a highly palatable food
(chocolate Ensure®) alters striatal enkephalin
gene expression. Eur. J. Neurosci. 18,
2592–2598 (2003).
138. Zhang, M., Balmadrid, C. & Kelley, A. E. Nucleus
accumbens opioid, GABAergic, and dopaminergic
modulation of palatable food motivation:
contrasting effects revealed by a progressive
ratio study in the rat. Behav. Neurosci. 117,
202–211 (2003).
139. Woolley, J. D., Lee, B. S., Taha, S. A. &
Fields, H. L. Nucleus accumbens opioid
signaling conditions short-term flavor
preferences. Neuroscience 146, 19–30 (2007).
140. Katsuura, Y. & Taha, S. A. Modulation of feeding
and locomotion through mu and delta opioid
receptor signaling in the nucleus accumbens.
Neuropeptides 44, 225–232 (2010).
141. Katsuura, Y., Heckmann, J. A. & Taha, S. A.
μ‑Opioid receptor stimulation in the nucleus
accumbens elevates fatty tastant intake by
increasing palatability and suppressing satiety
signals. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 301, R244–R254 (2011).
142. Mena, J. D., Sadeghian, K. & Baldo, B. A.
Induction of hyperphagia and carbohydrate
intake by mu-opioid receptor stimulation in
circumscribed regions of frontal cortex.
J. Neurosci. 31, 3249–3260 (2011).
143. Hagan, M. M. & Moss, D. E. An animal model
of bulimia nervosa: opioid sensitivity to fasting
episodes. Pharmacol. Biochem. Behav. 39,
421–422 (1991).
144. Boggiano, M. M. et al. Combined dieting and
stress evoke exaggerated responses to opioids
in binge-eating rats. Behav. Neurosci. 119,
1207–1214 (2005).
145. Naleid, A. M., Grace, M. K., Chimukangara, M.,
Billington, C. J. & Levine, A. S. Paraventricular
opioids alter intake of high-fat but not high-
sucrose diet depending on diet preference in
a binge model of feeding. Am. J. Physiol. Regul.
Integr. Comp. Physiol. 293, R99–R105 (2007).
146. Katsuura, Y. & Taha, S. A. Mu opioid receptor
antagonism in the nucleus accumbens shell
blocks consumption of a preferred sucrose
solution in an anticipatory contrast paradigm.
Neuroscience 261, 144–152 (2014).
147. Rao, R. E., Wojnicki, F. H., Coupland, J.,
Ghosh, S. & Corwin, R. L. Baclofen, raclopride,
and naltrexone differentially reduce solid fat
emulsion intake under limited access
conditions. Pharmacol. Biochem. Behav. 89,
581–590 (2008).
148. Giuliano, C., Robbins, T. W., Nathan, P. J.,
Bullmore, E. T. & Everitt, B. J. Inhibition of opioid
transmission at the μ‑opioid receptor prevents
both food seeking and binge-like eating.
Neuropsychopharmacology 37, 2643–2652
(2012).
149. Lenard, N. R., Zheng, H. & Berthoud, H. R.
Chronic suppression of μ‑opioid receptor
signaling in the nucleus accumbens attenuates
development of diet-induced obesity in rats.
Int. J. Obes. (Lond.) 34, 1001–1010 (2010).
150. Shin, A. C., Pistell, P. J., Phifer, C. B. &
Berthoud, H. R. Reversible suppression of food
reward behavior by chronic mu-opioid receptor
antagonism in the nucleus accumbens.
Neuroscience 170, 580–588 (2010).
151. Cottone, P., Sabino, V., Steardo, L. & Zorrilla, E. P.
Opioid-dependent anticipatory negative contrast
and binge-like eating in rats with limited access to
© 2014 Macmillan Publishers Limited. All rights reserved
highly preferred food. Neuropsychopharmacology
33, 524–535 (2008).
152. Yeomans, M. R. & Gray, R. W. Selective effects
of naltrexone on food pleasantness and intake.
Physiol. Behav. 60, 439–446 (1996).
153. Yeomans, M. R. & Gray, R. W. Effects of
naltrexone on food intake and changes in
subjective appetite during eating: evidence
for opioid involvement in the appetizer effect.
Physiol. Behav. 62, 15–21 (1997).
154. Bertino, M., Beauchamp, G. K. & Engelman, K.
Naltrexone, an opioid blocker, alters taste
perception and nutrient intake in humans. Am. J.
Physiol. 261, R59–R63 (1991).
155. Hetherington, M. M., Vervaet, N., Blass, E.
& Rolls, B. J. Failure of naltrexone to affect
the pleasantness or intake of food.
Pharmacol. Biochem. Behav. 40, 185–90 (1991).
156. Drewnowski, A., Krahn, D. D., Demitrack, M. A.,
Nairn, K. & Gosnell, B. A. Naloxone, an opiate
blocker, reduces the consumption of sweet high-
fat foods in obese and lean female binge eaters.
Am. J. Clin. Nutr. 61, 1206–1212 (1995).
157. Mitchell, J. E. et al. A placebo-controlled,
double‑blind crossover study of naltrexone
hydrochloride in outpatients with normal weight
bulimia. J. Clin. Psychopharmacol. 9, 94–97
(1989).
158. Alger, S. A., Schwalberg, M. D., Bigaouette, J. M.,
Michalek, A. V. & Howard, L. J. Effect of a tricyclic
antidepressant and opiate antagonist on binge-
eating behavior in normoweight bulimic and
obese, binge-eating subjects. Am. J. Clin. Nutr.
53, 865–871 (1991).
159. Chatoor, I., Herman, B. H. & Hartzler, J. Effects
of the opiate antagonist, naltrexone, on binging
antecedents and plasma β‑endorphin
concentrations. J. Am. Acad. Child Adolesc.
Psychiatry 33, 748–752 (1994).
160. Marrazzi, M. A., Bacon, J. P., Kinzie, J. &
Luby, E. D. Naltrexone use in the treatment of
anorexia nervosa and bulimia nervosa. Int. Clin.
Psychopharmacol. 10, 163–172 (1995).
161. Marrazzi, M. A., Markham, K. M., Kinzie, J. &
Luby, E. D. Binge eating disorder: response to
naltrexone. Int. J. Obes. Relat. Metab. Disord. 19,
143–145 (1995).
162. Jonas, J. M. & Gold, M. S. The use of opiate
antagonists in treating bulimia: a study of
low‑dose versus high-dose naltrexone.
Psychiatry Res. 24, 195–199 (1988).
163. Raingeard, I., Courtet, P., Renard, E. & Bringer, J.
Naltrexone improves blood glucose control in
type 1 diabetic women with severe and chronic
eating disorders. Diabetes Care 27, 847–848
(2004).
164. Neumeister, A., Winkler, A. & Wober-Bingol, C.
Addition of naltrexone to fluoxetine in the
treatment of binge eating disorder. Am. J.
Psychiatry 156, 797 (1999).
165. Daubenmier, J. et al. A new biomarker of hedonic
eating? A preliminary investigation of cortisol
and nausea responses to acute opioid blockade.
Appetite 74, 92–100 (2014).
166. McElroy, S. L. et al. A placebo-controlled pilot
study of the novel opioid receptor antagonist
ALKS‑33 in binge eating disorder. Int. J. Eat.
Disord. 46, 239–245 (2013).
167. Davis, C. et al. Opiates, overeating and obesity:
a psychogenetic analysis. Int. J. Obes. (Lond.) 35,
1347–1354 (2011).
168. Haghighi, A. et al. Opioid receptor μ 1 gene, fat
intake and obesity in adolescence. Mol.
Psychiatry 19, 63–68 (2014).
169. Davis, C. A. et al. Dopamine for “wanting” and
opioids for “liking”: a comparison of obese
adults with and without binge eating. Obesity
(Silver Spring) 17, 1220–1225 (2009).
www.nature.com/nrendo

170. Hatsukami, D., Owen, P., Pyle, R. & Mitchell, J.
Similarities and differences on the MMPI
between women with bulimia and women with
alcohol or drug abuse problems. Addict. Behav.
7, 435–439 (1982).
171. Leon, G. R., Kolotkin, R. & Korgeski, G.
MacAndrew Addiction Scale and other MMPI
characteristics associated with obesity, anorexia
and smoking behavior. Addict. Behav. 4,
401–407 (1979).
172. Scott, D. W. Alcohol and food abuse: some
comparisons. Br. J. Addict. 78, 339–349 (1983).
173. Tuomisto, T. et al. Psychological and physiological
characteristics of sweet food “addiction”. Int. J.
Eat. Disord. 25, 169–175 (1999).
174. Cassin, S. E. & von Ranson, K. M. Is binge
eating experienced as an addiction? Appetite 49,
687–690 (2007).
175. Goodman, A. Addiction: definition and
implications. Br. J. Addict. 85, 1403–1408 (1990).
176. Curtis, C. & Davis, C. A qualitative study of binge
eating and obesity from an addiction
perspective. Eat. Disord. 22, 19–32 (2014).
177. Lent, M. R. & Swencionis, C. Addictive
personality and maladaptive eating behaviors
in adults seeking bariatric surgery. Eat. Behav.
13, 67–70 (2012).
178. Davis, C. et al. ‘Food addiction’ and its
association with a dopaminergic multilocus
genetic profile. Physiol. Behav. 118, 63–69
(2013).
179. Burmeister, J. M., Hinman, N., Koball, A.,
Hoffmann, D. A. & Carels, R. A. Food addiction
in adults seeking weight loss treatment.
Implications for psychosocial health and
weight loss. Appetite 60, 103–110 (2013).
180. Gearhardt, A. N. et al. Neural correlates of food
addiction. Arch. Gen. Psychiatry 68, 808–816
(2011).
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  13
181. Meule, A. Food addiction and body‑mass‑index:
a non-linear relationship. Med. Hypotheses 79,
508–511 (2012).
182. Eichen, D. M., Lent, M. R., Goldbacher, E.
& Foster, G. D. Exploration of “food addiction”
in overweight and obese treatment-seeking
adults. Appetite 67, 22–24 (2013).
183. Gearhardt, A. N., Roberto, C. A., Seamans, M. J.,
Corbin, W. R. & Brownell, K. D. Preliminary
validation of the Yale Food Addiction Scale
for children. Eat. Behav. 14, 508–512 (2013).
184. Mason, S. M., Flint, A. J., Field, A. E.,
Austin, S. B. & Rich-Edwards, J. W. Abuse
victimization in childhood or adolescence
and risk of food addiction in adult women.
Obesity (Silver Spring) 21, E775–E781 (2013).
185. Meule, A., Lutz, A., Vögele, C. & Kübler, A.
Women with elevated food addiction symptoms
show accelerated reactions, but no impaired
inhibitory control, in response to pictures of
high‑calorie food-cues. Eat. Behav. 13, 423–428
(2012).
186. Murphy, C. M., Stojek, M. K. & MacKillop, J.
Interrelationships among impulsive personality
traits, food addiction, and body mass index.
Appetite 73, 45–50 (2014).
187. Gearhardt, A. N., White, M. A., Masheb, R. M.
& Grilo, C. M. An examination of food addiction
in a racially diverse sample of obese patients
with binge eating disorder in primary care
settings. Compr. Psychiatry 54, 500–505
(2013).
188. Meule, A. & Kübler, A. Food cravings in food
addiction: the distinct role of positive
reinforcement. Eat. Behav. 13, 252–255 (2012).
189. Bégin C. et al. Does food addiction distinguish
a specific subgroup of overweight/obese
overeating women? Health 4, 1492–1499
(2012).
© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
190. Berridge, K. C., Robinson, T. E. & Aldridge, J. W.
Dissecting components of reward: ‘liking’,
‘wanting’, and learning. Curr. Opin. Pharmacol. 9,
65–73 (2009).
191. Lent, M. R., Eichen, D. M., Goldbacher, E.,
Wadden, T. A. & Foster, G. D. Relationship of food
addiction to weight loss and attrition during
obesity treatment. Obesity (Silver Spring) 22,
52–55 (2014).
192. Ziauddeen, H. & Fletcher, P. C. Is food addiction
a valid and useful concept? Obes. Rev. 14,
19–28 (2013).
193. Clark, S. M. & Saules, K. K. Validation of the
Yale Food Addiction Scale among a weight-loss
surgery population. Eat. Behav. 14, 216–219
(2013).
194. Meule, A., Heckel, D. & Kübler, A. Factor
structure and item analysis of the Yale Food
Addiction Scale in obese candidates for bariatric
surgery. Eur. Eat. Disord. Rev. 20, 419–422
(2012).
195. Gearhardt, A. N., Corbin, W. R. & Brownell, K. D.
Preliminary validation of the Yale Food
Addiction  Scale. Appetite 52, 430–436
(2009).
196. Meule, A., Vögele, C. & Kübler, A. German
Translation and Validation of the Yale Food
Addiction Scale [German]. Diagnostica 58,
115–126 (2012).
197. Flint, A. J. et al. Food addiction scale
measurement in 2 cohorts of middle-aged and
older women. Am. J. Clin. Nutr. 99, 578–586
(2014).
Author contributions
S.M. and A.T. researched data for the Review.
S.M., A.T. and N.M.A. were involved in the writing
of the paper. All authors contributed to the review
and editing of the manuscript.