miRNA signatures associated with vulnerability to food addiction in mice and humans.

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.

Association of the dopamine D2 receptor rs1800497 polymorphism with food addiction, food reinforcement, and eating behavior in Chilean adults.

PURPOSE: The regulation of food intake and body weight involves two interacting systems: (a) The homeostatic system (including biological regulators of hunger and satiety) and (b) the non-homeostatic system, (involving concepts of food reinforcement and food addiction). Studies have established a strong genetic component in eating behavior and obesity. The TaqI A1 polymorphism (rs1800497) has previously been associated with eating behavior, diminished dopamine D2 receptor (DRD2) density, higher body mass, and food reinforcement, but relations to food addiction remain unclear. AIM: To evaluate the association between the polymorphism rs1800497 with eating behavior, food reinforcement and food addiction in Chilean adults. METHODS: This cross-sectional study recruited a convenience sample of 97 obese, 25 overweight and 99 normal-weight adults (18-35 years). Anthropometric measurements were performed by standard procedures. Eating behavior was assessed using the: Yale Food Addiction Scale (YFAS), the Three Factor Eating Behavior Questionnaire and the Food Reinforcement Value Questionnaire (FRVQ). The DRD2 genotype (rs1800497) was determined by taqman assays. RESULTS: Twenty-two percentage of the participants met the criteria for food addiction. Food addiction was higher in women than men (26% vs 10.7%) and in obese compared to non-obese (40% vs 6%). There was no relationship between food addiction and DRD2 genotype. However when stratified by sex and nutritional status, obese female carriers of the A1 allele reported greater scores on emotional eating and snack food reinforcement compared to non-carriers. CONCLUSIONS: The DRD2 polymorphism is associated with some hedonic aspects of eating behavior, namely food reinforcement and emotional eating but not food addiction, and this association may be moderated by sex and obesity status, with obese women who are carriers of this genetic variant at higher risk. LEVEL OF EVIDENCE: Level V: evidence obtained from a cross-sectional descriptive study.

Transcriptional signatures in prefrontal cortex confer vulnerability versus resilience to food and cocaine addiction-like behavior.

Addiction is a chronic relapsing brain disease characterized by compulsive reward-seeking despite harmful consequences. The mechanisms underlying addiction are orchestrated by transcriptional reprogramming in the reward system of vulnerable subjects. This study aims at revealing gene expression alterations across different types of addiction. We analyzed publicly available transcriptome datasets of the prefrontal cortex (PFC) from a palatable food and a cocaine addiction study. We found 56 common genes upregulated in the PFC of addicted mice in these two studies, whereas most of the differentially expressed genes were exclusively linked to either palatable food or cocaine addiction. Gene ontology analysis of shared genes revealed that these genes contribute to learning and memory, dopaminergic synaptic transmission, and histone phosphorylation. Network analysis of shared genes revealed a protein-protein interaction node among the G protein-coupled receptors (Drd2, Drd1, Adora2a, Gpr6, Gpr88) and downstream targets of the cAMP signaling pathway (Ppp1rb1, Rgs9, Pde10a) as a core network in addiction. Upon extending the analysis to a cell-type specific level, some of these common molecular players were selectively expressed in excitatory neurons, oligodendrocytes, and endothelial cells. Overall, computational analysis of publicly available whole transcriptome datasets provides new insights into the molecular basis of addiction-like behaviors in PFC.

Converging vulnerability factors for compulsive food and drug use.

Highly palatable foods and substance of abuse have intersecting neurobiological, metabolic and behavioral effects relevant for understanding vulnerability to conditions related to food (e.g., obesity, binge eating disorder) and drug (e.g., substance use disorder) misuse. Here, we review data from animal models, clinical populations and epidemiological evidence in behavioral, genetic, pathophysiologic and therapeutic domains. Results suggest that consumption of highly palatable food and drugs of abuse both impact and conversely are regulated by metabolic hormones and metabolic status. Palatable foods high in fat and/or sugar can elicit adaptation in brain reward and withdrawal circuitry akin to substances of abuse. Intake of or withdrawal from palatable food can impact behavioral sensitivity to drugs of abuse and vice versa. A robust literature suggests common substrates and roles for negative reinforcement, negative affect, negative urgency, and impulse control deficits, with both highly palatable foods and substances of abuse. Candidate genetic risk loci shared by obesity and alcohol use disorders have been identified in molecules classically associated with both metabolic and motivational functions. Finally, certain drugs may have overlapping therapeutic potential to treat obesity, diabetes, binge-related eating disorders and substance use disorders. Taken together, data are consistent with the hypotheses that compulsive food and substance use share overlapping, interacting substrates at neurobiological and metabolic levels and that motivated behavior associated with feeding or substance use might constitute vulnerability factors for one another. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.

What can we learn from PWS and SNORD116 genes about the pathophysiology of addictive disorders?

Addictive disorders have been much investigated and many studies have underlined the role of environmental factors such as social interaction in the vulnerability to and maintenance of addictive behaviors. Research on addiction pathophysiology now suggests that certain behavioral disorders are addictive, one example being food addiction. Yet, despite the growing body of knowledge on addiction, it is still unknown why only some of the individuals exposed to a drug become addicted to it. This observation has prompted the consideration of genetic heritage, neurodevelopmental trajectories, and gene-environment interactions in addiction vulnerability. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which children become addicted to food and show early social impairment. PWS is caused by the deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene was identified as the minimal gene responsible for the PWS phenotype. Several studies have also indicated the role of the Snord116 gene in animal and cellular models to explain PWS pathophysiology and phenotype (including social impairment and food addiction). We thus present here the evidence suggesting the potential involvement of the SNORD116 gene in addictive disorders.

Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications.

The role of stress, trauma, and adversity particularly early in life has been identified as a contributing factor in both drug and food addictions. While links between traumatic stress and substance use disorders are well documented, the pathways to food addiction and obesity are less established. This review focuses on psychosocial and neurobiological factors that may increase risk for addiction-like behaviors and ultimately increase BMI over the lifespan. Early childhood and adolescent adversity can induce long-lasting alterations in the glucocorticoid and dopamine systems that lead to increased addiction vulnerability later in life. Allostatic load, the hypothalamic-pituitary-adrenal axis, and emerging data on epigenetics in the context of biological embedding are highlighted. A conceptual model for food addiction is proposed, which integrates data on the biological embedding of adversity as well as upstream psychological, social, and environmental factors. Dietary restraint as a feature of disordered eating is discussed as an important contextual factor related to food addiction. Discussion of various public health and policy considerations are based on the concept that improved knowledge of biopsychosocial mechanisms contributing to food addiction may decrease stigma associated with obesity and disordered eating behavior.

A Distinct Brain-Gut-Microbiome Profile Exists for Females with Obesity and Food Addiction.

BACKGROUND: Alterations in brain-gut-microbiome interactions have been implicated as an important factor in obesity. This study aimed to explore the relationship between food addiction (FA) and the brain-gut-microbiome axis, using a multi-omics approach involving microbiome data, metabolomics, and brain imaging. METHODS: Brain magnetic resonance imaging was obtained in 105 females. FA was defined by using the Yale Food Addiction Scale. Fecal samples were collected for sequencing and metabolomics. Statistical analysis was done by using multivariate analyses and machine learning algorithms. RESULTS: Of the females with obesity, 33.3% exhibited FA as compared with 5.3% and 0.0% of females with overweight and normal BMI, respectively (P = 0.0001). Based on a multilevel sparse partial least square discriminant analysis, there was a difference in the gut microbiome of females with FA versus those without. Differential abundance testing showed Bacteroides, Megamonas, Eubacterium, and Akkermansia were statistically associated with FA (q < 0.05). Metabolomics showed that indolepropionic acid was inversely correlated with FA. FA was also correlated with increased connectivity within the brain's reward network, specifically between the intraparietal sulcus, brain stem, and putamen. CONCLUSIONS: This is the first study to examine FA along the brain-gut-microbiome axis and it supports the idea of targeting the brain-gut-microbiome axis for the treatment of FA and obesity.

Fenotipos de comportamiento alimentario: diseño de una nueva escala multidimensional (EFCA) / Eating behavior phenotypes: design of a new multidimensional scale (EFCA)

Introducción: las características conductuales de las personas juegan un papel importante en la heterogeneidad de la res-puesta al tratamiento de la obesidad. Existe evidencia de que ciertos rasgos de la conducta ingestiva humana serían media-dores entre la susceptibilidad genética individual y el exceso de peso corporal. Los fenotipos de comportamiento alimentario pueden utilizarse como predictores de éxito terapéutico. Para mejorar la eficacia de los tratamientos de la obesidad es nece-sario contar con herramientas prácticas que evalúen dichos fe-notipos para realizar abordajes personalizados o de precisión. Objetivos: diseñar y evaluar las propiedades psicométricas de una escala autoadministrada destinada a identificar fenotipos de comportamiento alimentario. Materiales y métodos: 177 sujetos adultos participaron vo-luntariamente en un estudio de validación de una escala au-toadministrada para identificar fenotipos comportamentales en adultos (Escala de Fenotipos de Comportamiento Alimentario, EFCA). La misma consta de 16 ítems que evalúan creencias y actitudes personales de la conducta ingestiva medidos a partir de una escala de Likert de cinco valores (1. nunca a 5. siempre). Se identificaron cinco factores por análisis paralelo y se realizó un análisis factorial exploratorio por máxima verosimilitud con rotación varimax como método de extracción. Resultados: se incluyeron 177 adultos, 75,7% mujeres, 75% con exceso de peso con media de índice de masa corporal (IMC) 30,46 kg/m2 (DE=7,06). La estructura factorial mostró buen ajuste a los datos, con cargas factoriales superiores a .40 en to-dos los casos. El coeficiente Alpha de Cronbach indicó fiabilidad aceptable de .86 para la escala total y entre .73 y .88 para las subescalas obtenidas. Conclusiones: la EFCA es una escala con niveles aceptables de validez y confiabilidad para identificar fenotipos de comporta-miento alimentario en adultos.

A specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction.

Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is associated with enhanced synaptic excitatory transmission in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc). In contrast, chemogenetic inhibition of neuronal activity in the mPFC-NAc pathway induces compulsive food seeking. Transcriptomic analysis and genetic manipulation identified that increased dopamine D2 receptor expression in the mPFC-NAc pathway promotes the addiction-like phenotype. Our study unravels a new neurobiological mechanism underlying resilience and vulnerability to the development of food addiction, which could pave the way towards novel and efficient interventions for this disorder.

The prevalence of food addiction and its associations with plasma oxytocin level and anthropometric and dietary measurements in Iranian women with obesity.

Obesity is a prevalent public health problem, and food addiction (FA) is one of the most controversial factors in its management. Therefore, this study was designed to validate an FA questionnaire for Iranian women with obesity and to determine the prevalence of FA and its associations with plasma oxytocin (OT) levels as well as anthropometric and dietary measurements. In this descriptive-analytical study, 450 adult women with obesity were included. The prevalence of FA was determined with a valid Yale food addiction scale (YFAS). Macronutrient intakes were measured by a valid semi-quantitative food frequency questionnaire (FFQ). In addition, plasma OT was measured after eight hours of fasting. In this study, the prevalence of FA was 26.2% in women with obesity. In comparison with class I obesity, the odds ratios (95% CI) of FA for class II and class III obesity were 2.5 (CI: 1.29-5.09) and 3.3 (CI: 1.69-6.4) respectively. Dietary intakes of energy, protein, carbohydrate, fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, and cholesterol were significantly higher in food-addicted (FAD) women compared to non-food-addicted (NFA) ones (p < 0.001). Moreover, plasma OT level was lower in FAD women with obesity than in NFA subjects (p = 0.02). In conclusion, the results of this study indicate that FA is prevalent in Iranian women with obesity. In addition, FA is related to obesity severity, dietary intakes of energy, carbohydrate, protein, fat, cholesterol, and plasma OT level.

Dopamine genetic risk is related to food addiction and body mass through reduced reward-related ventral striatum activity.

The prevalence rate of obesity continues to rise in the U.S., but effective treatment options remain elusive resulting in increased emphasis on prevention. One such area of prevention research capitalizes on the relatively novel behavioral construct of food addiction, which has been implicated in obesity. Food addiction reflects an individual's propensity for compulsive eating despite negative consequences, and shares not only symptoms with both eating and substance use disorders but also genetic and neural correlates within neural reward-circuitry modulated by dopamine. Here, we examined associations between food addiction scores, body mass index (BMI), reward-related ventral striatum activity, and a polygenic score approximating dopamine signaling in 115 non-Hispanic Caucasian young adult university students. As predicted, polygenic dopamine scores were related to ventral striatum activity, which in turn was associated with higher food addiction scores. In addition, food addiction was related to BMI. An exploratory post-hoc path analysis further indicated that polygenic scores were indirectly related to both food addiction and BMI, in part, through ventral striatum activity. Collectively, our results provide evidence supporting the utility of food addiction in weight gain prevention research by establishing links with known risk-related neural and genetic biomarkers.

Food Addiction and Binge Eating: Lessons Learned from Animal Models.

The feeding process is required for basic life, influenced by environment cues and tightly regulated according to demands of the internal milieu by regulatory brain circuits. Although eating behaviour cannot be considered "addictive" under normal circumstances, people can become "addicted" to this behaviour, similarly to how some people are addicted to drugs. The symptoms, cravings and causes of "eating addiction" are remarkably similar to those experienced by drug addicts, and both drug-seeking behaviour as eating addiction share the same neural pathways. However, while the drug addiction process has been highly characterised, eating addiction is a nascent field. In fact, there is still a great controversy over the concept of "food addiction". This review aims to summarize the most relevant animal models of "eating addictive behaviour", emphasising binge eating disorder, that could help us to understand the neurobiological mechanisms hidden under this behaviour, and to improve the psychotherapy and pharmacological treatment in patients suffering from these pathologies.

Similarities and Differences in Genetics.

Similar symptomatology manifestations and high co-morbidity in substance and non-substance addictions suggest that there may be a common pathogenesis between them. Associated with impulse control and emotional processing, the monoamine neurotransmitter system genes are suggested to be related to both substance and non-substance addictions, such as dopamine (DA) system, 5-hydroxytryptamine/serotonin (5-HT) system, the endogenous opioid system and so on. Here we reviewed the similarities and differences in genetics between classic substance addiction and common types of non-substance addiction, e.g. pathological gambling, Internet addiction, binge-eating disorder etc. It is necessary to systematically compare genetic mechanisms of non-substance addiction and substance addiction, which could reveal similarities and differences of substance addiction and non-addictive substances essentially, enhance our understanding of addiction theory and improve clinical practice with research results.

Two novel candidate genes identified in adults from the Newfoundland population with addictive tendencies towards food.

Food addiction (FA) is a distinguished clinical feature affecting about 5% adults of the general population in Canada. FA contributes to obesity, however, the underlying genes in FA are largely unknown. The aim of the current study was to search for FA candidate genes using an exome sequencing followed by a verification study using the most significantly associated identified genes. From a total of 752 adults, 24 subjects were selected including 8 obese with high and 8 obese with low/zero FA clinical symptom score (FAO, NFO), and 8 healthy controls with normal BMI and low/zero FA symptom score (Ctrl). Exome sequencing was completed in all three groups. The top 100 SNPs identified were categorized into 5 subgroups based on gene functions: addiction (Ad), psychological disorders, energy metabolism and obesity, and cancer, unknown function or with other diseases. In the verification study, the top 19 SNPs in the Addiction subgroup were genotyped in the entire 752 subjects using Sequenom iPLEX Gold genotyping technology. Comparison of NFO with Ctrl, and FAO with NFO, Ctrl and the combined group of NFO + Ctrl revealed 19 SNPs associated with Ad genes including, TIRAP, MMADHC, ERAP1, NTM, MYPN, GRID1, ITPR2, GPSM1, ZCCHC14, TNN, PPARD, CACNA1C, SIM1, and DRD2. Genetic association analysis was performed. The major allele A of rs2511521 located in DRD2 (OR = 3.1(95% CI 1.1-8.2)) and the minor allele T of rs625413 located in TIRAP (OR = 2.5(95% CI 1.1-5.8)) in NFO subjects significantly associated with increased risk of food addiction. Using a combination of exome sequencing method and a candidate gene association approach two new FA candidate genes are identified. Further study on the rest of the genes in the other four categories will be warranted.