The neurobiology of food intake in an obesogenic environment (2012)

Conditioned food intake in the absence of metabolic need

As we are increasingly exposed to cues evoking memories and images of foods throughout the day, this happens more and more frequently when we are satiated and metabolically replete. It is not clear how this hedonic hunger can be induced in the absence of metabolic depletion signals or during the postprandial phase when there is still plenty of absorbable energy in the gut. Why are we not simply ignoring such cues and stimuli? Several explanations are possible.

A model for cue-induced, conditioned food intake in satiated rats was developed by Weingarten⁽²⁴⁾. After temporally pairing a tone or light (conditioned stimulus, CS⁺) with the presentation of a retractable food cup in food-restricted animals, rats learned quickly to go to the food cup every time the CS⁺ was on. After rats had been returned to ad libitum feeding and were fully satiated, the CS⁺ continued to elicit food cup approach and a small meal⁽²⁴⁾, closely mimicking conditioned food intake through external cues in human subjects. In a series of elegant studies, Petrovich demonstrated the importance of a neural network including the amygdala, medial prefrontal cortex and lateral hypothalamus for this phenomenon to occur^(25–27). It appears that inputs to the hypothalamus from both the amygdala and medial prefrontal cortex (see Fig. 1) are necessary to link specific conditioned stimuli to appetitive action. It will be interesting to investigate the role of lateral hypothalamic orexin neurons and their projections to the mesolimbic dopamine system, as these neurons have been implicated in μ-opioid-induced food intake⁽²⁸⁾, depletion-induced salt intake⁽²⁹⁾ and reinstatement of drug seeking⁽³⁰⁾. As the lateral hypothalamus is a major behavioural and autonomic output venue for the mediobasal hypothalamic integrative energy sensor, this modulatory input from the amygdala and prefrontal cortex may provide a basis for the overriding of homoeostatic regulation by external signals. However, it should be noted that neither the Weingarten⁽²⁴⁾ nor the Petrovich studies⁽²⁵⁾ tested whether prolonged repetition of CS⁺ exposure led to chronic overeating and development of obesity and whether transection of the critical amygdala-hypothalamic projections prevented it.

 

Fig. 1. (colour online) Major neural systems and pathways involved in the control of ingestive behaviour and energy balance regulation with emphasis on interactions between the classical homoeostatic energy regulatory system in the hypothalamus and brainstem (blue boxes and arrows in lower half) and cognitive/emotional brain systems (red boxes and arrows in upper half). Bottom-up modulation of cognitive and emotional processes by metabolic signals and their derivatives is accomplished by (a) circulating hormones and metabolites acting not only on the hypothalamus and brainstem but also on external sensory processing pathways as well as on components of the corticolimbic system (open blue arrows with broken lines), (b) a stream of vagal and spinal sensory information from within the body to all levels of the neuraxis, including the cortex (full blue arrows with solid lines) and (c) neural signals generated by the integrative hypothalamic energy sensor and distributed to areas involved in reward-based decision making (full blue arrows with solid lines). Together, these ascending modulatory influences determine the level of incentive salience directed to specific nutrients. Top-down modulation of food intake and energy expenditure by cognitive and emotional/reward systems is accomplished by (a) direct external (taste and smell) sensory input to the hypothalamic energy sensor and response allocator (dark yellow lines), (b) input from the amygdala, cortex and reward processing systems to mainly the lateral hypothalamus, responsible for conditioned external signals to elicit food intake (full red lines and arrows), (c) inputs from cortex, amygdala and basal ganglia to midbrain extrapyramidal motor pathways (emotional motor system, broken red lines and full arrows) and (d) pyramidal motor system for voluntary behavioural control (broken red lines on the right). N. Accumbens, nucleus accumbens; SMA, supplemental motor area; BLA, basolateral amygdala; CeA, central nucleus of the amygdala; VTA, ventral tegmental area; PAG, periaqueductal gray; GLP-1, glucgon-like-peptide-1; PYY, peptide YY; AT, adipose tissue; SPA, spontaneous physical activity. Adapted from⁽¹²⁾.

The phenomenon of sensory-specific satiety⁽³¹⁾ may facilitate conditioned food intake in the satiated state. An example of this facilitation is the appeal of a new sensory food experience, typically dessert, at the end of a satiating meal. Little is known regarding the neural mechanisms involved in this phenomenon, but it has been shown that a reduction in the electrical activity of neurons in the orbitofrontal cortex, a part of the frontal cortex, of macaque monkeys, can reflect sensory-specific satiety⁽³²⁾. It is conceivable that some of the neurons in the orbitofrontal cortex direct their output to the lateral hypothalamus and thereby amplify vulnerability to conditioned food cues between meals.

It is also possible that the so-called cephalic phase responses to the sight and smell (or just thinking about) food can trigger appetitive behaviour ^{(33, 34)}. Perhaps the small increases in saliva, gastric acid, insulin and ghrelin secretion that constitute the cephalic response stimulate appetitive drive by acting on sensory nerves or directly on the brain and thereby enhance the neural effects of conditioned stimuli. We may also be more vulnerable to conditioned food cues when under stress. Food consumption as a form of self-medication to relieve stress has been demonstrated⁽³⁵⁾, although we do not know the neural mechanisms involved. Finally, a history of uncertainty about the food supply could also increase reactivity to food cues in the absence of direct metabolic hunger.

In summary, it has been clearly shown that conditioned stimuli can induce food intake in satiated rats and some of the critical neural circuitry has been identified. Thus, stimuli from the environment clearly have the capacity to temporarily overwhelm homoeostatic regulation. However, there is no animal or human study directly demonstrating that long-term exposure to conditioned stimuli leads to obesity.

Amplification of hedonic hunger by metabolic need

When conditioned cues such as food advertisements are present at times of metabolic depletion such as shortly before or during a meal, they are more likely to stimulate overingestion, because metabolic depletion amplifies their incentive salience^{(36, 37)}. It is well known that metabolic hunger makes us more responsive to cues signalling food and drug reward^{(38, 39)}. The neural pathways and mechanisms involved in this attribution of salience are not completely understood, but progress has recently been made. Specifically, it has been demonstrated that metabolic depletion signals in the form of high levels of circulating ghrelin as well as low levels of leptin, insulin, gut hormones and various metabolites can act not only on the classical brain areas involved in energy balance homoeostasis such as the hypothalamus and brainstem but also on brain areas involved in sensory processing, cognition and reward (Fig. 1; also see⁽⁴⁰⁾ for a more detailed discussion).

Neural representations of the pleasure of eating

It is clear that the reward value of food is not only represented by its taste and flavour during the consumatory phase. A variety of sensory stimuli and emotional states or feelings with vastly different temporal profiles contribute to the experience of reward. Specifically, during the post-consumatory phase, nutrients interact with sensors in the gastrointestinal tract, other peripheral organs and the brain itself. It has recently been demonstrated that when all taste processing is eliminated by genetic manipulation, mice still learn to prefer sugar over water, suggesting the generation of food reward by processes of glucose utilisation⁽⁵⁰⁾.

Given the multifaceted involvement of pleasure and reward in ingestive behaviour, it is clear that multiple neural systems are involved (for a more detailed analysis, see⁽⁵¹⁾). Briefly, the most primitive form of liking and disliking appears to be inherent to components of the peripheral gustatory pathways in the brainstem^(52–55). However, for the full sensory impact of palatable food and the subjective feeling of pleasure in human subjects, taste is integrated with other sensory modalities such as smell and mouth-feel. Integration takes place in forebrain areas including the amygdala, as well as primary and higher order sensory cortical areas including the insular and orbitofrontal cortex, where sensory representations of particular foods are formed^(56–62). The exact neural pathways through which such sensory percepts or representations lead to the generation of subjective pleasure are not clear. Neuroimaging studies in human subjects suggest that pleasure, as measured by subjective ratings, is computed within portions of the orbitofrontal and perhaps insular cortex^{(55, 63)}.

Neural systems representing the motivation to eat

The ultimate goal of food advertisement is to entice an individual to buy a specific food product and get hooked on it. This goal can be linked to what happens in addiction to drugs and alcohol, and it is not surprising that similar neural mechanisms have been implicated. Although ‘liking’ a branded food item seems necessary, ‘wanting’ it and buying it is more important for successful marketing. According to the liking/wanting distinction in food reward, it is possible to ‘want’ something that is not liked⁽⁶⁴⁾. Berridge defined wanting as ‘Incentive salience, or motivation for reward typically triggered by reward-related cues’⁽³⁶⁾. The mesolimbic dopamine system with projections from the ventral tegmental area to the nucleus accumbens, prefrontal cortex, amygdala and hippocampus seems to be a key neural substrate for wanting (Fig. 1). Phasic activity of dopamine neurons projecting from the ventral tegmental area to the nucleus accumbens in the ventral striatum is involved in the decision-making process during the preparatory (appetitive) phase of ingestive behaviour^{(65, 66)}. In addition, when palatable foods such as sucrose are actually consumed, a sustained and sweetness-dependent increase and turnover in dopamine levels occurs in the nucleus accumbens^(67–69). Dopamine signalling in the nucleus accumbens thus appears to play a role in both the appetitive and consumatory phases of an ingestive bout. The nucleus accumbens shell is thereby part of a neural loop including the lateral hypothalamus and the ventral tegmental area, with orexin neurons playing a key role^{(28, 70–74)}. This loop appears to be important for transmitting metabolic state signals from the lateral hypothalamus and thus attributing incentive salience to goal objects, as discussed earlier.

Eating and ‘free will’

In human subjects, there is also wanting at a more conscious level, described by Berridge as a ‘cognitive desire for a declarative goal in the ordinary sense of the word wanting’⁽³⁶⁾. In addition to the mesolimbic dopamine system, a number of cortical areas, such as the dorsolateral prefrontal cortex and other components of a decision-making system are likely involved⁽⁷⁵⁾. Ultimately, a conscious decision can be made to eat a food item or to abstain from eating it. Although this appears to be up to the ‘free will’ of every individual, even apparently conscious decisions may have a subconscious component. This was demonstrated in a neuroimaging study in human subjects which was designed to decode the outcome of decisions before and after they reached awareness⁽⁷⁶⁾. Notably, when the subject’s decision reached conscious awareness, it already had been influenced for up to 10 s by unconscious (unaware) brain activity in the lateral and medial frontopolar as well as anterior cingulate cortex and the precuneus⁽⁷⁶⁾. That prefrontal activity is necessary to choose advantageously in a gambling task was shown in a study in patients with prefrontal lesions⁽⁷⁷⁾. Normal subjects began to choose advantageously before they realised which strategy worked best, and they exhibited anticipatory skin conductance responses before they knew explicitly that it was a risky choice. In contrast, prefrontal patients continued to make disadvantageous choices and never showed an anticipatory autonomic response⁽⁷⁷⁾. These findings strongly suggest that subconscious neural activity can guide ingestive behaviour before conscious explicit knowledge does. The neural pathways for behavioural and autonomic control that escapes awareness is not well understood. Nevertheless, pathways from various prefrontal cortical areas and particularly strong descending pathways from the amygdala to areas in the midbrain (including the periaqueductal grey), brain stem and spinal cord are known to be part of the emotional motor system that exist outside the bounds of conscious control^(78–80) (Fig. 1). Interestingly, many areas of the limbic system, including the cortex have direct, monosynaptic inputs to autonomic preganglionic neurons⁽⁸¹⁾, providing an avenue for subconscious modulation of peripheral organs involved in metabolic processes (Fig. 1).

Overlap of neural pathways for food intake and drug addiction

Based on the observation that dopamine receptor-2 availability within the dorsal striatum is similarly reduced in both obese subjects and cocaine addicts⁽⁸²⁾, a heated discussion about the similarities between food and drug addiction has ensued^(83–92).

As repeated exposure to drugs of abuse causes neuro-adaptive changes leading to elevations in reward thresholds (tolerance resulting in decreased reward) that drive accelerated drug intake^(93–98), similar neural and behavioural changes can be predicted from repeated exposure to addictive foods. For example, repeated sucrose access is known to up-regulate dopamine release⁽⁹⁹⁾ and dopamine transporter expression⁽¹⁰⁰⁾, as well as to change dopamine D1 and D2-receptor availability in the nucleus accumbens^{(99, 101)}. These changes may be responsible for the observed escalation of sucrose binging, cross-sensitisation to amphetamine-induced locomotor activity, withdrawal symptoms, such as increased anxiety and depression⁽⁹⁹⁾ and the reduced reinforcing efficacy of normal foods⁽¹⁰²⁾.

Exposure to a palatable cafeteria diet in Wistar rats led to sustained hyperphagia over 40 d and lateral hypothalamic electrical self-stimulation threshold increased in parallel to body weight gain⁽¹⁰³⁾. A similar insensitivity of the reward system was previously seen in addicted rats that self-administered intravenous cocaine or heroin^{(93, 94)}. Dopamine D2-receptor expression in the dorsal striatum was significantly reduced, in parallel to worsening of the reward threshold⁽¹⁰³⁾, to levels found in cocaine addicted rats⁽¹⁰⁴⁾. Interestingly, after 14 d of abstinence from the palatable diet, reward threshold did not normalise even though the rats were hypophagic and lost about 10% body weight⁽¹⁰³⁾. This is in contrast to the relatively rapid (about 48 h) normalisation in reward thresholds in rats that abstained from cocaine self-administration⁽⁹⁴⁾, and may indicate the presence of irreversible changes caused by the high-fat content of the diet (see next section). Given the observation that cocaine addicts and obese human subjects exhibit low D2-receptor availability in the dorsal striatum⁽¹⁰⁵⁾, dopamine plasticity due to repeated consumption of palatable food may be similar to what occurs with repeated consumption of drugs of abuse. On the other hand, there is less convincing evidence for development of dependence on high-fat food^{(106, 107)}, although intermittent access to corn oil can stimulate dopamine release in the nucleus accumbens⁽¹⁰⁸⁾.

Modern environment: less opportunity to burn energy

This review has almost entirely focused on energy intake, but it is clear that the modern environment also affects energy expenditure in a number of ways. Although we are beginning to understand the neurobiology of food intake in the modern world, we remain almost completely ignorant regarding the neurobiological controls of physical activity and exercise and the integrative processes that comprise the regulation of energy balance⁽¹³⁶⁾. One reason might be that we have a limited understanding of hormonal (or neural) inter-organ communication. Although we know a lot about gut–brain and adipose tissue–brain signalling, we know virtually nothing about communication between the exercising muscle and the brain and other organs. Only very recently, the muscle-derived hormone irisin was discovered which appears to induce browning of white adipose tissue⁽¹³⁷⁾. It will be interesting to see whether this hormone also signals to the brain systems regulating energy balance.