Obese humans, compared with normal-weight humans, have less striatal D2 receptors and striatal response to food intake; weaker striatal response to food predicts weight gain for individuals at genetic risk for reduced dopamine (DA) signaling, consistent with the reward-deficit theory of obesity. Yet these may not be initial vulnerability factors, as overeating reduces D2 receptor density, D2 sensitivity, reward sensitivity, and striatal response to food. Obese humans also show greater striatal, amygdalar, orbitofrontal cortex, and somatosensory region response to food images than normal-weight humans do, which predicts weight gain for those not at genetic risk for compromised dopamine signaling, consonant with the reward-surfeit theory of obesity. However, after pairings of palatable food intake and predictive cues, DA signaling increases in response to the cues, implying that eating palatable food contributes to increased responsivity. Using fMRI, we tested whether normal-weight adolescents at high- versus low-risk for obesity showed aberrant activation of reward circuitry in response to receipt and anticipated receipt of palatable food and monetary reward. High-risk youth showed greater activation in the caudate, parietal operculum, and frontal operculum in response to food intake and in the caudate, putamen, insula, thalamus, and orbitofrontal cortex in response to monetary reward. No differences emerged in response to anticipated food or monetary reward. Data indicate that youth at risk for obesity show elevated reward circuitry responsivity in general, coupled with elevated somatosensory region responsivity to food, which may lead to overeating that produces blunted dopamine signaling and elevated responsivity to food cues.

Although the intake of high-fat and high-sugar food activates mesolimbic reward, gustatory, and oral somatosensory brain regions, contributing to overeating, few studies have examined the relative role of fat and sugar in the activation of these brain regions, which would inform policy, prevention, and treatment interventions designed to reduce obesity. We evaluated the effect of a high-fat or high-sugar equicaloric chocolate milkshake and increasing fat or sugar milkshake content on the activation of these regions. Functional magnetic resonance imaging was used to assess the neural response to the intake of high-fat/high-sugar, high-fat/low-sugar, low-fat/high-sugar, and low-fat/low-sugar chocolate milkshakes and a tasteless solution in 106 lean adolescents (mean ± SD age = 15.00 ± 0.88 y). Analyses contrasted the activation to the various milkshakes. High-fat compared with high-sugar equicaloric milkshakes caused greater activation in the bilateral caudate, postcentral gyrus, hippocampus, and inferior frontal gyrus. High-sugar compared with high-fat equicaloric milkshakes caused greater activation in the bilateral insula extending into the putamen, the Rolandic operculum, and thalamus, which produced large activation regions. Increasing sugar in low-fat milkshakes caused greater activation in the bilateral insula and Rolandic operculum; increasing fat content did not elicit greater activation in any region. Fat caused greater activation of the caudate and oral somatosensory regions than did sugar, sugar caused greater activation in the putamen and gustatory regions than did fat, increasing sugar caused greater activity in gustatory regions, and increasing fat did not affect the activation. Results imply that sugar more effectively recruits reward and gustatory regions, suggesting that policy, prevention, and treatment interventions should prioritize reductions in sugar intake. This trial was registered at clinicaltrials.gov as DK092468.

Advances in neuroimaging techniques have provided insight into the role of the brain in the regulation of food intake and weight. Growing evidence demonstrate that energy dense, palatable foods elicit similar responses in rewardrelated brain regions that mimic those of addictive substances. Currently, various models of obesitys relation to reward from food have been theorized. There is evidence to support a theory of hypo-responsivity of reward regions to food, where individuals consume excess amounts to overcome this reward deficit. There is also data to support a theory of hyper-responsivity of reward regions, where individuals who experience greater reward from food intake are at risk for overeating. However, these seemingly discordant theories are static in nature and do not account for the possible effects of repeated overeating on brain responsivity to food and initial vulnerability factors. Here we review data that support these theories and propose a dynamic vulnerability model of obesity that appears to offer a parsimonious theory that accommodates extant findings.

The objective of the study was to test the hypotheses that humans with genotypes putatively associated with low dopamine (DA) signaling capacity, including the TaqIA A1 allele, DRD2-141C Ins/Ins genotype, DRD4 7-repeat or longer allele, DAT1 10-repeat allele, and the Met/Met COMT genotype, and with a greater number of these genotypes per a multilocus composite, show less responsivity of reward regions that primarily rely on DA signaling. Functional magnetic resonance imaging (fMRI) paradigms were used to investigate activation in response to receipt and anticipated receipt of palatable food and monetary reward. DNA was extracted from saliva using standard methods. Participants were 160 adolescents (mean age = 15.3 years, SD = 1.07 years; mean body mass index = 20.8, SD = 1.9). The main outcome was blood oxygenation level-dependent activation in the fMRI paradigms. Data confirmed that these fMRI paradigms activated reward, attention, somatosensory, and gustatory regions. Individuals with, versus without, these five genotypes did not show less activation of DA-based reward regions, but those with the Met/Met versus the Val/Val COMT genotype showed less middle temporal gyrus activation and those with the DRD4-L versus the DRD4-S genotype showed less middle occipital gyrus activation in response to monetary reward. Critically, the multilocus composite score revealed that those with a greater number of these genotypes showed less activation in reward regions, including the putamen, caudate, and insula, in response to monetary reward. The results suggest that the multilocus genetic composite is a more sensitive index of vulnerability for low reward region responsivity than individual genotypes.