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Obesity and The Brain: How Convincing Is The Addiction Model?
Obesity and The Brain: How Convincing Is The Addiction Model?
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It is possible, therefore, that there are the animal) increase and remain elevated occur as a consequence of, rather than a
some shared vulnerabilities between drug 2 weeks after cessation of the diet, indicat- cause of, increased BMI. More importantly,
addiction and obesity. However, this does not ing early and persistent alteration of reward subsequent PET studies have not produced
in itself strongly support an argument that thresholds54. These findings suggest the consistent findings.
the same processes occur in each condition. development of a reward-deficiency state In studies on normal-weight participants,
similar to that seen with drugs of abuse59,60. the act of consuming food was initially shown
Evidence from animal models. By far the Reductions in presynaptic dopamine have to be associated with a reduction in dopamine
strongest evidence for a food-addiction syn- also been shown in animals on cafeteria binding in the dorsal striatum to a degree that
drome comes from animal models50. Using diets, and their dopamine activity is reduced correlated with subjectively rated meal pleas-
highly palatable foods and highly structured in response to standard chow but not palat- antness66. However, in a subsequent study,
intermittent-access regimes, it has been able food61. A complementary finding is that the presence of food in the mouth was not
possible to induce an addiction-like pheno- obesity-prone animals have been shown to associated with a significant change in striatal
type in rats. Rats with intermittent access have lower baseline levels of dopamine62,63. dopamine binding, although high levels of
to high-sugar and high-fat foods develop In summary, highly controlled condi- dietary restraint were associated with greater
escalating, binge-like eating behaviours21,51, tions for short periods of time can produce food-induced alterations in dopamine-
a phenomenon that seems to be related to sugar dependence in rats, although this is receptor availability in the dorsal striatum67.
the palatability of the foods rather than their not associated with obesity. Conversely, the Furthermore, using an elegant combination
macronutrient composition52. However, this combination of high fat and high sugar can of drug challenge (methylphenidate com-
escalation of sugar and fat intake is offset produce a compulsive overeating syndrome, pared with placebo) and stimulus presenta-
by decreases in intake of their normal food accompanied by obesity and the develop- tion (food and neutral non-food stimuli), it
supply, so although these animals become ment of a negative anhedonic state. In both was shown that food stimulation alone does
‘addicted’, they do not become obese53. situations, there is a corresponding reduc- not always have an impact on D2R striatal
A different picture is seen when fat and tion in D2Rs. Notably, researchers who have binding and that, although food stimulation
sugar are combined (as in ‘cafeteria’ diets, carried out experiments evaluating food combined with a methylphenidate challenge
in which animals are fed on foods such as addiction in animals are at pains to point out is associated with reduced dopamine binding,
bacon, cheesecake and chocolate), where- that there are important differences between the same is true for the combination of meth-
upon increased consumption and weight the effects of foods and drugs (for example, ylphenidate and a neutral non-food stimulus
gain occur in the context of eating that dopamine release in response to drugs per- (and, moreover, binding changes produced
appears more compulsive54. sists across multiple administrations, whereas by the food–methylphenidate combination
In the case of sugar ‘addiction’, enforced dopamine release induced by palatable foods do not differ significantly from those found
abstinence is associated with enhanced ceases when the food is no longer novel or with a food–placebo combination)68. In
motivation towards food55. Moreover, a the animal is no longer hungry 21). The neces- short, PET data relating to dopamine bind-
withdrawal syndrome, which can be induced sity for highly specific food presentation in ing and food consumption in normal-weight
by challenge with the opioid antagonist order to engender addictive behaviours is people are inconsistent, although this may be
naloxone or by enforced abstinence, has also an important consideration64. Given that due, in part, to the different methodological
also been demonstrated56. The features of the environments of humans are much more approaches used, such as consuming versus
the syndrome — including teeth chattering, variable than those of laboratory animals, tasting food.
forepaw tremor and head shakes — along the degree to which models of food addiction Given the variability in dopamine respon-
with their induction by administration of in animals may extend to human obesity has sivity to food stimuli in normal-weight
an opioid antagonist, indicate an opioid- yet to be explored. humans, it is perhaps unsurprising that the
mediated effect of the high-sugar diet. In picture in obesity is also inconsistent. Even in
these withdrawal states, levels of dopamine Dopamine receptor studies in human obesity. the first study, which showed reduced D2R
in the accumbens fall and acetylcholine In 2001, a landmark PET study demon- availability in morbidly obese individuals
levels rise56. However, such a withdrawal strated reduced striatal D2R binding in a (BMI range 42–60), there was considerable
syndrome has not been demonstrated with group of obese individuals22. Importantly, overlap with binding measures in healthy-
high-fat and cafeteria diets51. D2R levels were negatively correlated with weight controls22. In a more recent study 69, a
How do these behavioural changes relate BMI. The ensuing inference, that obesity is comparable striatum-based analysis showed
to altered neural substrates? In animals characterized by striatal hypofunction, is no difference in baseline dopamine-binding
binge-eating on high-sugar diets, the dopa- consistent with a reward-deficiency account measures between overweight or obese
mine release that occurs with food exposure of overeating 22. The idea is that overeating individuals and normal-weight controls
fails to habituate with loss of novelty, even in arises because there is less hedonic value (although a subsequent voxel-wise analysis
those that are sham fed (food is consumed in food, leading to compensatory over- showed a thalamic difference that extended
orally but not digested because it is removed consumption. Complementing this was the into the striatum). The negative correlation
immediately by a gastric cannula)52,57. In observation that D2R binding correlated between BMI and striatal dopamine bind-
animals binge-eating on sugar and those fed with prefrontal metabolism65, suggesting ing was not replicated. There are, of course,
a cafeteria diet, striatal D2R levels fall54,58. that striatal hypofunction is compounded numerous reasons why one might expect dif-
Moreover, in the animals of the latter group, by reduced inhibitory control. This work ferences between the original sample, which
brain self-stimulation thresholds (the mini- has been important in developing the consisted of a group of people with a BMI of
mum intensity of electrical stimulation in addiction model of obesity, although such more than 40, and the more recent one, in
the lateral hypothalamus that will maintain correlative, cross-sectional observations which mean BMI was much less. For exam-
self-administration of the stimulation by do not tell us whether the receptor changes ple, peripheral metabolic profiles might be
quite different, as might food intake. But the also produced conflicting results, suggest- not the case. Although studies exploring
fact remains that reduced D2R binding ing both decreases and increases in recep- brain responses to food and food-related
is not a consistent correlate of BMI or tor binding subsequent to surgery 70,71. stimuli in normal-weight people have shown
obesity and, as such, this does not, as is In short, the message emerging from largely consistent activation in reward cir-
usually claimed, provide consistent evidence PET ligand studies is rather more complex cuitry (including the amygdala, insula and
in favour of the addiction hypothesis. than is frequently asserted. Although it has striatum), the pattern emerging from studies
Perhaps the inconsistency is a conse- been shown that dopamine ligand binding comparing obese individuals and binge-eaters
quence of the phenotypic complexity of is reduced in obese individuals, this finding with controls is most remarkable for its vari-
obesity. However, a study focusing specifi- has not been replicated, and studies involv- ability and inconsistency (TABLE 2). A more
cally on differences between binge eaters ing challenges with dopamine-stimulating specific prediction, based on the reward-
and BMI-matched controls20 demonstrated drugs and food-related stimuli produce deficiency hypothesis, is an enhancement
neither a correlation between receptor complex results that do not corroborate an of anticipatory responses and a reduction of
binding and BMI nor group differences addiction model. Nor does a narrowing of consummatory responses to food rewards
that accord with an addiction model. In the phenotypic question to BED do anything in obese individuals72. However, studies that
BED, the combination of a food stimulus to clarify matters. explicitly distinguish between anticipation-
and methylphenidate was associated with and consumption-related brain activity are
reduced dopamine binding in the caudate, Functional neuroimaging. Functional neuro rare, and their results are equivocal.
whereas in non-binge-eating obese indi- imaging is an important tool in testing the TABLE 2 summarizes key findings from
viduals only the combination of a non-food addiction model, which predicts that func- functional neuroimaging studies of children,
stimulus and methylphenidate produced a tional responses to foods and food-related adolescents and adults that explored brain
significant change. Other studies examin- stimuli in key reward-related brain regions responses to food-related stimuli (typically
ing the impact of bariatric surgery have should be consistently perturbed. This is images) and to anticipation and consumption
Table 2 | Summary of the findings of studies exploring altered brain responses in people with obesity or altered eating patterns
Brain region Response to cues signalling
Response to presentation of food imminent presentation of food/
images juice reward (anticipation) Response to consumption of reward
Obese BED BMI FA Obese BED BMI FA Obese BED BMI FA
Regions associated with the reward circuitry
Striatum 2 ↑83,84, 2 ↔87,88 1 ↑89, NA 1 ↑93, 1 ↔94 NA NA 1 ↑95 5 ↔93,94,96–98 1 ↓99, 1 ↓94 1 ↔95
1 ↓85, 1 ↓90, 1 ↔100
1 ↔86 3 ↔85,91,92
Midbrain 4 ↔83–86 2 ↔87,88 5 ↔85,89–92 NA 2 ↔93,94 NA NA 1 ↔95 1 ↑96, 2 ↔99,100 1 ↔94 1 ↔95
4 ↔93,94,97,98
PFC (orbital) 1 ↑86, 1 ↑87, 3 ↑90–92, NA 2 ↔93,94 NA NA 1 ↑95 1 ↑96, 1 ↓99, 1 ↔94 1 ↓95
3 ↔83–85 1 ↔88 1 ↓89, 4 ↔93,94,97,98 1 ↔100
1 ↔85
PFC (lateral) 3 ↑84–86, 2 ↔87,88 1 ↑85, NA 1 ↑93, 1 ↔94 1 ↑101 NA 1 ↔95 1 ↑93, 2 ↔99,100 1 ↔94 1 ↔95
1 ↔83 1 ↓92, 2 ↓97,98,
3 ↔89–91 2 ↔94,96
PFC (medial) 2 ↑84,86, 1 ↑87, 1 ↓92, NA 1 ↑94, 1 ↔93 NA NA 1 ↑95 5 ↔93,94,96–98 2 ↔99,100 1 ↔94 1 ↔95
1 ↓85, 1 ↔88 4 ↔85,89–91
1 ↔83
Amygdala 4 ↔83–86 2 ↔87,88 5 ↔85,89–92 NA 2 ↔93,94 NA NA 1 ↑95 1 ↑93, 1 ↓99, 1 ↔94 1 ↔95
4 ↔94,96–98 1 ↔100
Gustatory 1 ↑83, 1 ↑87, 3 ↑89,90,92, NA 1 ↑94, 1 ↔93 NA NA 1 ↔95 3 ↑93,94,96, 2 ↓99,100 1 ↔94 1 ↔95
cortex (AI/FO) 3 ↔84–86 1 ↓88 2 ↔85,91 2 ↔97,98
Hippocampus/ 2 ↑84,86, 2 ↔87,88 1 ↓85, NA 1 ↑93, 1 ↔94 NA NA 1 ↔95 5 ↔93,94,96–98 2 ↔99,100 1 ↔94 1 ↔95
PHG 1 ↓85, 4 ↔89–92
1 ↔83
Brain regions not associated with the reward circuitry
Thalamus 1 ↓85, 2 ↔87,88 5 ↔85,89–92 NA 2 ↔93,94 NA NA 1 ↔95 5 ↔93,94,96–98 2 ↔99,100 1 ↔94 1 ↔95
3 ↔83,84,86
Rolandic 4 ↔83–86 2 ↔87,88 5 ↔85,89–92 NA 2 ↑93,94 NA NA 1 ↔95 2 ↑93,94, 2 ↔99,100 1 ↔94 1 ↔95
operculum 3 ↔96–98
The table shows responses that were elevated (↑) or reduced (↓) in groups of obese individuals or those with binge-eating disorder (BED) relative to controls.
No group difference is signified by ‘↔’. Numbers before the arrows indicate the number of studies. The table also shows studies reporting positive (↑), negative (↓)
or no (↔) reported group difference between neural activity and body mass index (BMI) or food addiction (FA) scores. AI, anterior insula; FO, frontal operculum;
NA, no reports available (at the time of writing); PFC, prefrontal cortex; PHG, parahippocampal gyrus.
Food environment
Energy
expenditure
Appetite
• Availability and satiety
• Palatability
• Energy density • Impaired satiety
• Fat-free mass
• Portion size signalling
• Physical activity
• Insensitivity to
hunger and fullness
• Eating rate
Physical • Food access
environment • Access to physical Energy balance
activity
• Early developmental
• Advertising programming
• TV watching • Genetic and epigenetic
• Parental and societal • Reward sensitivity factors
influences • Impulsivity
• Media • Abnormal eating Individual
• Food addiction predispositions
Environmental
influences
Personality and
reward circuitry
Figure 1 | Mediators of energy balance and body weight. The outer require further exploration and refinement. The data on which the figure
Nature Reviews | Neuroscience
ring represents the major classes of mediators, the inner ring some of the is based come from the Obesity Systems Map introduced by the UK
individual mediators in each class. We suggest that food addiction is one Foresight programme 2007, a multidisciplinary effort to plan the
of many factors in a more complex model of the obesity epidemic that UK response to obesity82.
of actual food stimuli (typically milkshake). Functional neuroimaging allows us to overeating, let alone support for the addic-
A number of approaches have been used to measure not only regional responses but tion model? We find it hard to believe that
explore obesity and altered eating patterns. also inter-regional relationships. Alterations such circuitry is unaltered. One possibility
Case–control studies comparing obese indi- in these system-wide patterns have been is that overeating and its consequences are
viduals with normal-weight controls are typi- assessed in association with external food just too complex to expect consistency when
cal and are complemented by analyses of the sensitivity — the extent to which external individuals are grouped simply according to
extent to which activity correlates with BMI food cues evoke the desire to eat 73 — and BMI, or to binge-eating or food-addiction
and, in one study, with food-addiction score. obesity 74. Although intriguing observations scores. Given that obesity and binge eating
Studies of binge eating (with bulimia nervosa have been made, particularly with respect are complex phenotypes emerging for a
or BED) have also been carried out. The to the regions described above (which host of genetic and environmental reasons,
findings shown in TABLE 2 indicate a striking constitute the ‘reward circuitry’), it is too in failing to account for this complexity
lack of consistency across studies. soon to judge whether connectivity studies our capacity to identify group or factor-
Of course, there are differences in tasks will show a consistency that eludes regional related differences is markedly reduced.
and stimuli across the studies and there are measures. Furthermore, both of these phenotypes
age and gender differences across the groups There are two clear messages emerging have often been measured cross-sectionally,
studied. But, given that the striatum, mid- from the functional neuroimaging literature without taking into account the natural his-
brain and prefrontal cortex are core compo- on obesity and overeating. First, a growing tory of these conditions (BOX 2). We clearly
nents of the dopaminergic-reinforcement body of work has not supported any single need more precise behavioural, temporal,
circuitry, the lack of consistent findings across view of obesity and overeating. Second, metabolic, genetic and cognitive profiling in
a large set of studies militates strongly against even when analysis is confined to sub- such investigations. Moreover, the growing
the addiction model. If we consider the region groups showing binge-eating behaviour, sophistication of cognitive neuroscientific
of the anterior insula and frontal operculum there has been no convincing or consist- models of addictive behaviours points
that is sometimes referred to as the gusta- ent pattern of abnormal responding in the to crucial process-specific alterations in
tory cortex, the inconsistency remains. Nor reward circuitry. If the addiction model regional responding. Dissecting out these
is observation of responses in the amygdala of overeating has currency beyond phe- processes will require more complex task-
helpful in distinguishing obese individuals notypic similarities (which, as we argue dependent measurements than are typically
from normal-weight controls. The over- above, are themselves weak), we would applied in overeating and obese individuals.
whelming message emerging from TABLE 2, expect functional neuroimaging studies to In the future, those imaging studies that
even allowing for technical and participant identify core similarities. Why have they attempt to distinguish subtle processes and
differences, is that functional neuroimaging failed to provide any consistent insight into simultaneously take into account individual
does not support the addiction model. the behaviour of brain reward circuitry in variability 27 will prove useful and important.
Conclusions and future directions Hisham Ziauddeen and Paul C. Fletcher are in the 25. Lilenfeld, L. R. R., Ringham, R., Kalarchian, M. A. &
Department of Psychiatry, University of Cambridge, Marcus, M. D. A family history study of binge-eating
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argue that the work tells us three important Laboratories, Institute of Metabolic Science,
(2010).
Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
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e-mail: pcf22@cam.ac.uk
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