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Reward, dopamine and the control of food intake: implications for obesity

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The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated that this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control.

Introduction

One-third of the US adult population is obese [body mass index (BMI) ≥30 kg m−2] [1]. This fact has far reaching and costly implications, because obesity is strongly associated with serious medical complications (e.g. diabetes, heart disease, fatty liver and some cancers) [2]. Not surprisingly, the health care costs alone owing to obesity in the US have been estimated at close to US$150 billion [3].

Social and cultural factors undoubtedly contribute to this epidemic. Specifically, environments that promote unhealthy eating habits (ubiquitous access to highly processed and junk foods) and physical inactivity are believed to have a fundamental role in the widespread problem of obesity (Overweight and Obesity Website of the Centers for Disease Control and Prevention; http://www.cdc.gov/obesity/index.html). However, individual factors also help determine who will (or will not) become obese in these environments. Based on heredity studies, genetic factors are estimated to contribute between 45% and 85% of the variability in BMI 4, 5. Although genetic studies have revealed point mutations that are over-represented among obese individuals [4], for the most part, obesity is thought to be under polygenic control 6, 7. Indeed, the most recent whole genome-wide association analysis study (GWAS) conducted in 249,796 individuals of European descent identified 32 loci associated with BMI. However, these loci explained only 1.5% of the variance in BMI [8]. Moreover, it was estimated that GWAS studies with larger samples should be able to identify 250 extra loci with effects on BMI. However, even with the undiscovered variants, it was estimated that signals from common variant loci would account for only 6–11% of the genetic variation in BMI (based on an estimated heritability of 40–70%). The limited explanation of the variance from these genetic studies is likely to reflect the complex interactions between individual factors (as determined by genetics) and the way in which individuals relate to environments where food is widely available, not only as a source of nutrition, but also as a strong reward that by itself promotes eating [9].

The hypothalamus [via regulatory neuropeptides such as leptin, cholecystokinin (CCK), ghrelin, orexin, insulin, neuropeptide Y (NPY), and through the sensing of nutrients, such as glucose, amino acids and fatty acids] is recognized as the main brain region regulating food intake as it relates to caloric and nutrition requirements 10, 11, 12, 13. In particular, the arcuate nucleus through its connections with other hypothalamic nuclei and extra-hypothalamic brain regions, including the nucleus tractus solitarius, regulates homeostatic food intake [12] and is implicated in obesity 14, 15, 16 (Figure 1a, left panel). However, evidence is accumulating that brain circuits other than those regulating hunger and satiety are involved in food consumption and obesity [17]. Specifically, several limbic [nucleus accumbens (NAc), amygdala and hippocampus] and cortical brain regions [orbitofrontal cortex (OFC), cingulate gyrus (ACC) and insula] and neurotransmitter systems (dopamine, serotonin, opioids and cannabinoids) as well as the hypothalamus are implicated in the rewarding effects of food [18] (Figure 1a, right panel). By contrast, the regulation of food intake by the hypothalamus appears to rely on the reward and motivational neurocircuitry to modify eating behaviors 19, 20, 21.

Based on findings from imaging studies, a model of obesity was recently proposed in which overeating reflects an imbalance between circuits that motivate behavior (because of their involvement in reward and conditioning) and circuits that control and inhibit pre-potent responses [22]. This model identifies four main circuits: (i) reward–saliency; (ii) motivation–drive; (iii) learning–conditioning; and (iv) inhibitory control–emotional regulation–executive function. Notably, this model is also applicable to drug addiction. In vulnerable individuals, the consumption of high quantities of palatable food (or drugs in addiction) can upset the balanced interaction among these circuits, resulting in an enhanced reinforcing value of food (or drugs in addiction) and in a weakening of the control circuits. This perturbation is a consequence of conditioned learning and the resetting of reward thresholds following the consumption of large quantities of high-calorie foods (or drugs in addiction) by at-risk individuals. The undermining of the cortical top-down networks that regulate pre-potent responses results in impulsivity and in compulsive food intake (or compulsive drug intake in addiction). This paper discusses the evidence that links the neural circuits involved in top-down control with those involved with reward and motivation and their interaction with peripheral signals that regulate homeostatic food intake.

Section snippets

Food is a potent natural reward and conditioning stimulus

Certain foods, particularly those rich in sugars and fat, are potent rewards [23] that promote eating (even in the absence of an energetic requirement) and trigger learned associations between the stimulus and the reward (conditioning). In evolutionary terms, this property of palatable foods used to be advantageous because it ensured that food was eaten when available, enabling energy to be stored in the body (as fat) for future need in environments where food sources were scarce and/or

Disruption in reward and conditioning to food in overweight and obese individuals

Preclinical and clinical studies have provided evidence of decreases in DA signaling in striatal regions [decreases in DAD2 (D2R) receptors and in DA release], that are linked with reward (NAc) but also with habits and routines (dorsal striatum) in obesity 56, 57, 58. Importantly, decreases in striatal D2R have been linked to compulsive food intake in obese rodents [59] and with decreased metabolic activity in OFC and ACC in obese humans [60] (Figure 3a–c). Given that dysfunction in OFC and ACC

Evidence of cognitive disruption in overweight and obese individuals

There is increasing evidence that obesity is associated with impairment on certain cognitive functions, such as executive function, attention and memory 73, 74, 75. Indeed, the ability to inhibit the urges to eat desirable food varies among individuals and might be one of the factors that contribute to their vulnerability for overeating [34]. The adverse influence of obesity on cognition is also reflected in the higher prevalence of attention deficit hyperactivity disorder (ADHD) [76],

Food for thought

It would appear, from the collected evidence presented here, that a substantial fraction of obese individuals exhibit an imbalance between an enhanced sensitivity of the reward circuitry to conditioned stimuli linked to energy-dense food and impaired function of the executive control circuitry that weakens inhibitory control over appetitive behaviors. Regardless of whether this imbalance causes, or is caused by, pathological overeating, the phenomenon is reminiscent of the conflict between the

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