Genetically-predicted prefrontal DRD4 gene expression modulates differentiated brain responses to food cues in adolescent girls and boys

Andre K Portella,Richard S Lee,Susan Carnell,Liuyi Chen,Laurette Dube,Patricia P Silveira,Afroditi Papantoni,Antoneta T Joseph

doi:10.1038/s41598-021-02797-9

Abstract

The dopamine receptor 4 (DRD4) in the prefrontal cortex (PFC) acts to modulate behaviours including cognitive control and motivation, and has been implicated in behavioral inhibition and responsivity to food cues. Adolescence is a sensitive period for the development of habitual eating behaviors and obesity risk, with potential mediation by development of the PFC. We previously found that genetic variations influencing DRD4 function or expression were associated with measures of laboratory and real-world eating behavior in girls and boys. Here we investigated brain responses to high energy–density (ED) and low-ED food cues using an fMRI task conducted in the satiated state. We used the gene-based association method PrediXcan to estimate tissue-specific DRD4 gene expression in prefrontal brain areas from individual genotypes. Among girls, those with lower vs. higher predicted prefrontal DRD4 expression showed lesser activation to high-ED and low-ED vs. non-food cues in a distributed network of regions implicated in attention and sensorimotor processing including middle frontal gyrus, and lesser activation to low-ED vs non-food cues in key regions implicated in valuation including orbitofrontal cortex and ventromedial PFC. In contrast, males with lower vs. higher predicted prefrontal DRD4 expression showed minimal differences in food cue response, namely relatively greater activation to high-ED and low-ED vs. non-food cues in the inferior parietal lobule. Our data suggest sex-specific effects of prefrontal DRD4 on brain food responsiveness in adolescence, with modulation of distributed regions relevant to cognitive control and motivation observable in female adolescents.

Highlights

Adolescence is a key period for the development of eating behaviors that confer obesity r isk[1,2]
Maternal education was higher in the analytic sample (64.4% graduated from college) compared with the entire sample (55.7% graduated from college) (p = 0.003)
Females had significantly higher body fat percent compared to males (F(1,69) = 25.07, p < 0.001) across both DRD4 groups, and pubertal stage was more advanced in females, with females predominantly at the post pubertal stage, and males predominantly in mid and late pubertal stages (p < 0.001), with no evidence for differences by DRD4 group

Summary

Introduction

Adolescence is a key period for the development of eating behaviors that confer obesity r isk[1,2]. A similar differential susceptibility effect was found in the current adolescent cohort, such that lower predicted PFC DRD4 expression was associated with greater food intake in the satiated state, in the context of lower socioeconomic status[20] This approach represents a significant addition to existing work by examining specific effects of genetically-driven mechanisms on the biological substrate of interest, in this case brain circuits including and interacting with prefrontal cortex. Studies in females using fMRI have demonstrated that weaker responses in the brain reward circuitry to imagined and actual intake of palatable foods are more strongly associated with greater future increases in body mass in individuals carrying low functioning variants of dopamine receptor genes, such as the DRD2 TaqIA A1 allele and the DRD47R a llele[28,29]. Since obesity is associated with eating in the presence of s atiety[33], and with reduced neural satiety r esponses[32], we examined effects of DRD4 PFC expression on neural food cue responses in the satiated/fed, rather than the fasted, state

Methods

Results

Conclusion