Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating.

BACKGROUND: Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. METHODS: We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. RESULTS: C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. CONCLUSIONS: We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

Binge-type eating disrupts dopaminergic and GABAergic signaling in the prefrontal cortex and ventral tegmental area.

OBJECTIVE: Binge eating is characterized by repeated intermittent bouts of compulsive overconsumption of food. Treatment is challenging given limited understanding of the mechanisms underlying this type of disordered eating. The hypothesis that dysregulation of mesocortical dopaminergic and GABAergic systems underlie binge eating was tested. METHODS: Analysis of gene expression within the ventral tegmental area and its terminal mesocortical regions was examined in bingeing rats before and after bingeing occurred. In addition, alterations in binge-type behavior induced by pharmacological inactivation of subnuclei of the prefrontal cortex (PFC) and by pharmacological activation and inhibition of cortical D1 and D2 receptors were examined. RESULTS: Correlative and functional evidence demonstrates dysregulated neurotransmitter processing by the PFC and ventral tegmental area, but not the amygdala or nucleus accumbens, in bingeing rats. Either GABAergic inactivation or D2-like receptor activation within the PFC increased consumption in bingeing rats, but not controls, suggesting that the PFC, and D2 receptors in particular, functions as a behavioral brake to limit bingeing. CONCLUSIONS: The act of bingeing resolved some gene expression differences that preceded binge onset, further suggesting that bingeing may partially serve to self-medicate a system driving this maladaptive behavior. However, the failure of bingeing to resolve other dopaminergic/GABAergic differences may render individuals vulnerable to future binge episodes.

Decreased caudate response to milkshake is associated with higher body mass index and greater impulsivity.

Previous investigations consistently report a negative association between body mass index (BMI) and response in the caudate nucleus during the consumption of palatable and energy dense food. Since this response has also been linked to weight gain, we sought to replicate this finding and determine if the reduced response is associated with measures of impulsivity or food reward. Two studies were conducted in which fMRI was used to measure brain response to milkshake and a tasteless control solution. In Study 1 (n=25) we also assessed self-reported impulsivity, willingness to work for food, and subjective experiences of the pleasantness of milkshake taste and aroma. Replicating prior work, we report a negative association between BMI and brain response to milkshake vs. tasteless in the caudate nucleus. The opposite pattern was observed in the ventral putamen, with greater response observed in the 13 overweight compared to the 12 healthy weight subjects. Regression of brain response against impulsivity and food reward measures revealed one significant association: in the overweight but not healthy weight group self-reported impulsivity was negatively associated with caudate response to milkshake. In Study 2 (n=14), in addition to assessing brain response to milkshake and tasteless solutions subjects completed a go/no-go task outside the scanner. As predicted, we identified an inverse relationship between caudate response to milkshake vs. tasteless and failure to inhibit responses on the no-go trials. We conclude that the inverse correlation between BMI and caudate response to milkshake is associated with impulsivity but not food reward. These findings suggest that response to milkshake in the dorsal striatum may be related to weight gain by promoting impulsive eating behavior.

Rodent models of binge eating: are they models of addiction?

Are recently developed rodent models of binge eating also models of food addiction? Valid models should meet human criteria for both bingeing and substance dependence as described in the 4th edition and proposed for the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Similarly, behavioral profiles of bingeing animals should share characteristics with those of animal models of drug addiction. We evaluate and discuss current rodent models of bingeing, their contributions to scientific understanding of bingeing, their validity with respect to DSM criteria, and their overlap with models of addiction. The models described indicate that repeated intermittent bouts in which large quantities of fatty or sugary foods are consumed (binges) are associated with behavioral changes similar to those described for drugs of abuse. In contrast, control groups consuming the same foods in a nonbinge-type manner do not exhibit an "addiction-like" behavioral profile. Thus, fatty/sugary foods in and of themselves do not appear to have addictive qualities. Rather, the manner in which they are consumed appears to be critical. In addition, while rodent models of bingeing and drug self-administration share similarities, we do not support reclassifying the bingeing-related eating disorders as substance use disorders because of differences that distinguish such disorders in humans.