Elsevier

NeuroImage

Volume 50, Issue 4, 1 May 2010, Pages 1618-1625
NeuroImage

Reward circuitry responsivity to food predicts future increases in body mass: Moderating effects of DRD2 and DRD4

https://doi.org/10.1016/j.neuroimage.2010.01.081Get rights and content

Abstract

Objective

To determine whether responsivity of reward circuitry to food predicts future increases in body mass and whether polymorphisms in DRD2 and DRD4 moderate these relations.

Design

The functional magnetic resonance imaging (fMRI) paradigm investigated blood oxygen level dependent activation in response to imagined intake of palatable foods, unpalatable foods, and glasses of water shown in pictures. DNA was extracted from saliva samples using standard salting-out and solvent precipitation methods.

Participants

Forty-four adolescent female high school students ranging from lean to obese.

Main Outcome

Future increases in body mass index (BMI).

Results

Weaker activation of the frontal operculum, lateral orbitofrontal cortex, and striatum in response to imagined intake of palatable foods, versus imagined intake of unpalatable foods or water, predicted future increases in body mass for those with the DRD2 TaqIA A1 allele or the DRD4–7R allele. Data also suggest that for those lacking these alleles, greater responsivity of these food reward regions predicted future increases in body mass.

Discussion

This novel prospective fMRI study indicates that responsivity of reward circuitry to food increases risk for future weight gain, but that genes that impact dopamine signaling capacity moderate the predictive effects, suggesting two qualitatively distinct pathways to unhealthy weight gain based on genetic risk.

Introduction

Theorists posit that hyper-responsivity of the mesolimbic and mesocortical circuitry that encodes food reward increases risk for obesity (Davis et al., 2004). Functional magnetic resonance imaging (fMRI) studies indicate that obese versus lean individuals show greater activation in the insula, frontal operculum, lateral orbitofrontal cortex (OFC), amygdala, and striatum in response to pictures of palatable foods (Rothemund et al., 2007, Stoeckel et al., 2008) and anticipated receipt of palatable food (Stice et al., 2008b). Data suggest that the insula and frontal operculum are involved in food craving and anticipated reward from food, and further that the OFC, amygdala, and striatum encode the reward value of food (Gottfried et al., 2003, Small et al., 2008). However, because the fMRI studies that have investigated the relation of anticipatory food reward to obesity have been cross-sectional, it is unclear whether hyper-responsivity of this circuitry increases risk for future weight gain or is a result of conditioning from overeating palatable foods. Thus, we tested whether hyper-responsivity of food reward regions increases risk for future increases in body mass.

Other theorists argue that some individuals show hypo-responsivity of reward circuitry, which prompts them to overeat to compensate for this deficiency (Comings and Blum, 2000). Positron emission tomography (PET) studies find that obese versus lean individuals show less D2 receptor binding in the striatum (Volkow et al., 2008, Wang et al., 2001), which suggests that they have fewer D2 receptors. Dopamine is involved in the reinforcing effects of food; feeding results in dopamine release in the dorsal striatum and the degree of pleasure from eating correlates with amount of dopamine release (Small et al., 2003). Dopamine antagonists increase food intake and produce weight gain, whereas dopamine agonists reduce energy intake and produce weight loss (Epstein et al., 2007). Yet, consumption of a high-fat, high-sugar diet may lead to down-regulation of D2 receptors. Repeated intake of sweet and fatty foods results in down-regulation of post-synaptic D2 receptors, increased D1 receptor binding, and decreased D2 sensitivity and μ-opioid receptor binding in animals (Bello et al., 2002, Colantuoni et al., 2001), paralleling neural response to chronic use of drugs that increase dopamine signaling. Thus, it is important to test whether hypo-responsivity of reward circuitry increases risk for future weight gain. One prospective study found that when mice are exposed to a high-fat diet, those with lower D2 receptor density in the putamen showed more weight gain than mice with higher D2 receptor density in this region (Huang et al., 2006). In a prospective fMRI study we found that individuals who showed weaker striatal activation in response to receipt of palatable food were at elevated risk for increases in body mass over a 1-year follow-up, but only if they had an Al allele of the TaqIA SNP (rs1800497) in the DRD2 gene (Stice et al., 2008a). The Taq1A polymorphism has three allelic variants: A1/A1, A1/A2, and A2/A2. Individuals with an A1/A1 or A1/A2 TaqIA genotype have 30–40% fewer striatal D2 receptors than those with the A2/A2 genotype (Ritchie and Noble, 2003, Tupala et al., 2003). The TaqIA A1 genotype is also associated with hypofunctioning of the prefrontal cortex, hypothalamus, striatum, insula, and amygdala (Bowirrat and Oscar-Berman, 2005, Noble, 2003). The DRD2 TaqIA A1 genotype has correlated with body mass in some studies (Spitz et al., 2000, Thomas et al., 2001), but other studies have not found a significant main effect (Jenkinson et al., 2000, Southon et al., 2003).

Given the evidence that weaker striatal activation in response to food intake predicts future increases in body mass if coupled with the DRD2 TaqIA A1 genotype, we used blood oxygen level dependent (BOLD) fMRI to test whether activation of brain reward regions in response to imagined intake of palatable foods predicts future increases in body mass and whether these relations were moderated by genotypes associated with a potential reduction in dopamine signaling. We examined brain activation in response to imagined intake of a range of palatable foods because our previous fMRI paradigm (Stice et al., 2008a) examined only activation in response to chocolate milkshake. In addition to investigating the DRD2 TaqIA gene, we examined the 48-base pair (bp) exon 3 Variable Number Tandem Repeat (VNTR) polymorphism in the DRD4 gene. DRD4 is a postsynaptic receptor that is principally inhibitory of the second messenger adenylate cyclase. D4 receptors are localized in areas innervated by mesocortical projections from the ventral tegmental area, including the prefrontal cortex, cingulate gyrus, and insula (Noaín et al., 2006). The 7-repeat or longer VNTR allele (DRD4–7R) has been associated with compromised dopamine functioning in an in vitro study (Asghari et al., 1995), poorer response to dopamine stimulating drugs (Hamarman et al., 2004), and less dopamine release in the ventral caudate and nucleus accumbens after cigarette use (Brody et al., 2006). Humans with versus without one or more DRD4 long (7R–10R) alleles have shown higher maximum lifetime body mass in samples at risk for obesity (Guo et al., 2007, Kaplan et al., 2008, Levitan et al., 2004), as well as greater food cravings in response to food cues (Sobik et al., 2005), smoking cravings and activation of the superior frontal gyrus and insula in response to smoking cues (McClernon et al., 2007), alcohol cravings and activation in OFC, anterior cingulate gyrus, and striatum in response to alcohol (Hutchison et al., 2002, Filbey et al., 2008), and heroin craving in response to heroin cues (Shao et al., 2006).

Section snippets

Participants

Participants were 44 adolescent girls (M age = 15.6; SD = 0.96; 2.3% African Americans, 84.1% European Americans, 4.5% Native Americans, and 9.1% mixed racial heritage) recruited from a larger study of female high schools students who reported body image concerns to participate in a study on the neural response to presentation of food (see also Stice et al., 2008b). Those who reported binge eating or compensatory behavior in the past 3 months, any use of psychotropic medications or illicit drugs,

Results

Baseline BMI correlated positively with activation in the left putamen (r = 0.56; p < 0.001 Figs. 1A–B) and right lateral OFC (r = 0.51, p < 0.01) during exposure to appetizing versus unappetizing foods and with activation in the OFC (r = 0.50, p < 0.01; r = 60; p < 0.001 Figs. 1C–D) and frontal operculum (r = 0.55 and 0.56) during exposure to appetizing food versus water (Table 1). Presence of the A1 allele (Fig. 2) significantly moderated the relation between baseline BMI and increased response in the right

Discussion

The prospective interactive effects suggest that individuals who show weaker activation of brain reward circuitry in response to imagined intake of palatable foods are at elevated risk for future weight gain if they possess the TaqIA1 allele of the DRD2 gene or the exon 3 7-repeat allele of the DRD4 gene, presumably because they have reduced dopamine signaling. These findings dovetail with evidence that weaker striatal activation in response to receipt of palatable food increases risk for

Acknowledgments

This research was supported by a Roadmap Supplement for Interdisciplinary Research in Behavioral and Biological Sciences (R1MH64560A).

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