A dual-omics approach on the effects of fibroblast growth factor-2 (FGF-2) on ventral tegmental area dopaminergic neurons in response to alcohol consumption in mice.

Harmful alcohol consumption is a major socioeconomic burden to the health system, as it can be the cause of mortality of heavy alcohol drinkers. The dopaminergic (DAergic) system is thought to play an important role in the pathogenesis of alcohol drinking behaviour; however, its exact role remains elusive. Fibroblast growth factor 2 (FGF-2), a neurotrophic factor, associated with both the DAergic system and alcohol consumption, may play an important role in DAergic neuroadaptations during alcohol abuse. Within this study, we aimed to clarify the role of endogenous FGF-2 on the DAergic system and whether there is a possible link to alcohol consumption. We found that lack of FGF-2 reduces the alcohol intake of mice. Transcriptome analysis of DAergic neurons revealed that FGF-2 knockout (FGF-2 KO) shifts the molecular fingerprint of midbrain dopaminergic (mDA) neurons to DA subtypes of the ventral tegmental area (VTA). In line with this, proteomic changes predominantly appear also in the VTA. Interestingly, these changes led to an altered regulation of the FGF-2 signalling cascades and DAergic pathways in a region-specific manner, which was only marginally affected by voluntary alcohol consumption. Thus, lack of FGF-2 not only affects the gene expression but also the proteome of specific brain regions of mDA neurons. Our study provides new insights into the neuroadaptations of the DAergic system during alcohol abuse and, therefore, comprises novel targets for future pharmacological interventions.

Repeated binge-like eating episodes in female rats alter adenosine A2A and dopamine D2 receptor genes regulation in the brain reward system.

OBJECTIVE: Binge-eating disorder is an eating disorder characterized by recurrent binge-eating episodes, during which individuals consume excessive amounts of highly palatable food (HPF) in a short time. This study investigates the intricate relationship between repeated binge-eating episode and the transcriptional regulation of two key genes, adenosine A2A receptor (A2AAR) and dopamine D2 receptor (D2R), in selected brain regions of rats. METHOD: Binge-like eating behavior on HPF was induced through the combination of food restrictions and frustration stress (15 min exposure to HPF without access to it) in female rats, compared to control rats subjected to only restriction or only stress or none of these two conditions. After chronic binge-eating episodes, nucleic acids were extracted from different brain regions, and gene expression levels were assessed through real-time quantitative PCR. The methylation pattern on genes' promoters was investigated using pyrosequencing. RESULTS: The analysis revealed A2AAR upregulation in the amygdala and in the ventral tegmental area (VTA), and D2R downregulation in the nucleus accumbens in binge-eating rats. Concurrently, site-specific DNA methylation alterations at gene promoters were identified in the VTA for A2AAR and in the amygdala and caudate putamen for D2R. DISCUSSION: The alterations on A2AAR and D2R genes regulation highlight the significance of epigenetic mechanisms in the etiology of binge-eating behavior, and underscore the potential for targeted therapeutic interventions, to prevent the development of this maladaptive feeding behavior. These findings provide valuable insights for future research in the field of eating disorders. PUBLIC SIGNIFICANCE: Using an animal model with face, construct, and predictive validity, in which cycles of food restriction and frustration stress evoke binge-eating behavior, we highlight the significance of epigenetic mechanisms on adenosine A2A receptor (A2AAR) and dopamine D2 receptor (D2R) genes regulation. They could represent new potential targets for the pharmacological management of eating disorders characterized by this maladaptive feeding behavior.

Blunted reward prediction error signals in internet gaming disorder.

BACKGROUND: Internet gaming disorder (IGD) is a type of behavioural addictions. One of the key features of addiction is the excessive exposure to addictive objectives (e.g. drugs) reduces the sensitivity of the brain reward system to daily rewards (e.g. money). This is thought to be mediated via the signals expressed as dopaminergic reward prediction error (RPE). Emerging evidence highlights blunted RPE signals in drug addictions. However, no study has examined whether IGD also involves alterations in RPE signals that are observed in other types of addictions. METHODS: To fill this gap, we used functional magnetic resonance imaging data from 45 IGD and 42 healthy controls (HCs) during a reward-related prediction-error task and utilised a psychophysiological interaction (PPI) analysis to characterise the underlying neural correlates of RPE and related functional connectivity. RESULTS: Relative to HCs, IGD individuals showed impaired reinforcement learning, blunted RPE signals in multiple regions of the brain reward system, including the right caudate, left orbitofrontal cortex (OFC), and right dorsolateral prefrontal cortex (DLPFC). Moreover, the PPI analysis revealed a pattern of hyperconnectivity between the right caudate, right putamen, bilateral DLPFC, and right dorsal anterior cingulate cortex (dACC) in the IGD group. Finally, linear regression suggested that the connection between the right DLPFC and right dACC could significantly predict the variation of RPE signals in the left OFC. CONCLUSIONS: These results highlight disrupted RPE signalling and hyperconnectivity between regions of the brain reward system in IGD. Reinforcement learning deficits may be crucial underlying characteristics of IGD pathophysiology.

Brain Mechanisms of Exercise-Induced Hypoalgesia: To Find a Way Out from "Fear-Avoidance Belief".

It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain.

Maladaptive brain organization at 1 month into abstinence as an indicator for future relapse in patients with alcohol use disorder.

Abstinence is a lifelong endeavor, and the risk of a relapse is always present for patients with Alcohol Use Disorder (AUD). The aim of the study was to better understand specific characteristics of the intrinsic whole-brain-network architecture of 34 AUD patients that may support abstinence or relapse. We used Graph Theory Analysis (GTA) of resting-state fMRI data from treatment seekers at 1 month of abstinence and their follow-up data as abstainers or relapsers 3 months later, together with data from 30 light/non-drinking controls scanned at the same interval. We determined the group-specific intrinsic community configurations at both timepoints as well as the corresponding modularity Q, a GTA measure that quantifies how well individual network communities are separated from each other. Both AUD groups at both timepoints had community configurations significantly different from those of controls, but the three groups did not significantly differ in their Q values. However, relapsers showed a maladaptive community configuration at baseline, which became more similar to the controls' community organization after the relapsers had started consuming alcohol again during the study interval. Additionally, successful recovery from AUD was not associated with re-gaining the intrinsic brain organization found in light/non-drinkers, but with a re-configuration resulting in a new brain organization distinctly different from that of healthy controls. Resting-state fMRI provides useful measures reflecting neuroplastic adaptations related to AUD treatment outcome.

Neuromodulation in Psychiatric disorders: Experimental and Clinical evidence for reward and motivation network Deep Brain Stimulation: Focus on the medial forebrain bundle.

Deep brain stimulation (DBS) in psychiatric illnesses has been clinically tested over the past 20 years. The clinical application of DBS to the superolateral branch of the medial forebrain bundle in treatment-resistant depressed patients-one of several targets under investigation-has shown to be promising in a number of uncontrolled open label trials. However, there are remain numerous questions that need to be investigated to understand and optimize the clinical use of DBS in depression, including, for example, the relationship between the symptoms, the biological substrates/projections and the stimulation itself. In the context of precision and customized medicine, the current paper focuses on clinical and experimental research of medial forebrain bundle DBS in depression or in animal models of depression, demonstrating how clinical and scientific progress can work in tandem to test the therapeutic value and investigate the mechanisms of this experimental treatment. As one of the hypotheses is that depression engenders changes in the reward and motivational networks, the review looks at how stimulation of the medial forebrain bundle impacts the dopaminergic system.

The gray matter structural connectome and its relationship to alcohol relapse: Reconnecting for recovery.

Gray matter (GM) atrophy associated with alcohol use disorders (AUD) affects predominantly the frontal lobes. Less is known how frontal lobe GM loss affects GM loss in other regions and how it influences drinking behavior or relapse after treatment. The profile similarity index (PSI) combined with graph analysis allows to assess how GM loss in one region affects GM loss in regions connected to it, ie, GM connectivity. The PSI was used to describe the pattern of GM connectivity in 21 light drinkers (LDs) and in 54 individuals with AUD (ALC) early in abstinence. Effects of abstinence and relapse were determined in a subgroup of 36 participants after 3 months. Compared with LD, GM losses within the extended brain reward system (eBRS) at 1-month abstinence were similar between abstainers (ABST) and relapsers (REL), but REL had also GM losses outside the eBRS. Lower GM connectivities in ventro-striatal/hypothalamic and dorsolateral prefrontal regions and thalami were present in both ABST and REL. Between-networks connectivity loss of the eBRS in ABST was confined to prefrontal regions. About 3 months later, the GM volume and connectivity losses had resolved in ABST, and insula connectivity was increased compared with LD. GM losses and GM connectivity losses in REL were unchanged. Overall, prolonged abstinence was associated with a normalization of within-eBRS connectivity and a reconnection of eBRS structures with other networks. The re-formation of structural connectivities within and across networks appears critical for cognitive-behavioral functioning related to the capacity to maintain abstinence after outpatient treatment.

Neuroplasticity and Multilevel System of Connections Determine the Integrative Role of Nucleus Accumbens in the Brain Reward System.

A growing body of evidence suggests that nucleus accumbens (NAc) plays a significant role not only in the physiological processes associated with reward and satisfaction but also in many diseases of the central nervous system. Summary of the current state of knowledge on the morphological and functional basis of such a diverse function of this structure may be a good starting point for further basic and clinical research. The NAc is a part of the brain reward system (BRS) characterized by multilevel organization, extensive connections, and several neurotransmitter systems. The unique role of NAc in the BRS is a result of: (1) hierarchical connections with the other brain areas, (2) a well-developed morphological and functional plasticity regulating short- and long-term synaptic potentiation and signalling pathways, (3) cooperation among several neurotransmitter systems, and (4) a supportive role of neuroglia involved in both physiological and pathological processes. Understanding the complex function of NAc is possible by combining the results of morphological studies with molecular, genetic, and behavioral data. In this review, we present the current views on the NAc function in physiological conditions, emphasizing the role of its connections, neuroplasticity processes, and neurotransmitter systems.

Neuromedin U, a Key Molecule in Metabolic Disorders.

Obesity is now a public health concern. The leading cause of obesity is an energy imbalance between ingested and expended calories. The mechanisms of feeding behavior and energy metabolism are regulated by a complex of various kinds of molecules, including anorexigenic and orexigenic neuropeptides. One of these neuropeptides, neuromedin U (NMU), was isolated in the 1980s, and its specific receptors, NMUR1 and NMUR2, were defined in 2000. A series of subsequent studies has revealed many of the physiological roles of the NMU system, including in feeding behavior, energy expenditure, stress responses, circadian rhythmicity, and inflammation. Particularly over the past decades, many reports have indicated that the NMU system plays an essential and direct role in regulating body weight, feeding behavior, energy metabolism, and insulin secretion, which are tightly linked to obesity pathophysiology. Furthermore, another ligand of NMU receptors, NMS (neuromedin S), was identified in 2005. NMS has physiological functions similar to those of NMU. This review summarizes recent observations of the NMU system in relation to the pathophysiology of obesity in both the central nervous systems and the peripheral tissues.

Food additives, food and the concept of 'food addiction': Is stimulation of the brain reward circuit by food sufficient to trigger addiction?

In the last few years, the concept of 'food addiction' has continued to gain popularity, with human and animal studies demonstrating the differential effects of foods that are high in fat, sugar or protein on appetite, satiety, eating behaviour and the development of food addiction. However, a number of studies have disputed the occurrence of food addiction in humans. Questions have also arisen regarding the possible impacts that food additives may have on the development of food addiction or eating disorders. Also, it is known that alterations in food composition and the presence of food additives (flavour enhancers, sugars, sugar substitutes, and non-nutritive sweeteners) are factors that generally influence the sensory perception of food. Our understanding of the potential roles of central neurotransmitters (such as dopamine) and certain neuropeptides in the evolution of food addiction is also evolving; but presently, there isn't sufficient scientific evidence to consider any food ingredient, micronutrient or standard food-additive as addictive. In this review, the relevant literatures dealing with the concept of 'food addiction' are examined, and the factors which may predispose to food addiction are discussed. The possible influences that flavour-enhancers, sugars, sugar substitutes and non-nutritive sweeteners may exert on central neurotransmission, neurotransmitter/receptor interactions, appetite, satiety, conditioned- preferences and the brain reward system are also highlighted.

Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice.

BACKGROUND: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. METHODS: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. RESULTS: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. CONCLUSION: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Association study of the SLC6A3 VNTR (DAT) and DRD2/ANKK1 Taq1A polymorphisms with alcohol dependence in a population from northeastern Brazil.

BACKGROUND: Alcohol dependence (AD) is a complex psychiatric disorder, affecting 5.4% of the general population lifetime, characterized by excessive alcohol consumption influenced by environmental risk factors and genetic factors. Genetic alterations in dopaminergic system are involved in the treatment and etiology of AD. The aim of this search was to test the association of the SLC6A3 40 bp-VNTR and DRD2/ANKK1 Taq1A single nucleotide polymorphism (SNP), a transporter and receptor of the dopaminergic system, with AD through a study in a population of northeastern Brazil. METHODS: The study design was a case-control that included 227 males of northeastern Brazil (113 alcoholics and 114 controls). Alcoholics were classified according to the DSM-IV criteria for AD and controls were subjects who had nonalcohol problems or who never drank. Genotyping was detected through polymerase chain reaction (PCR) for SLC6A3 40 bp-VNTR and RFLP-PCR for DRD2/ANKK1 Taq1A, and subsequent electrophoresis on a 2% agarose gel. The distribution of allele and genotype frequencies and association of polymorphisms with AD were assessed by chi-square, Fisher's exact test, and odds ratio (OR) with a confidence interval of 95% and significance p < 0.05. Data were analyzed on BioEstat 5.3 software. RESULTS: The SLC6A3 40 bp-VNTR was associated with AD, allelic, and genotypic frequencies were significantly different, respectively (A9 vs. A10: OR = 1.88; p = 0.01; A9/A9 vs. A10/A10: OR = 6.25; p = 0.02; A9/A9 vs. A9/A10 + A10A10: OR = 5.44; p = 0.03). However, there was no statistically significant difference when the allelic (p = 0.10) and genotypic (p > 0.05) frequencies for DRD2/ANKK1 Taq1A were compared. CONCLUSIONS: These findings suggest that A9 allele and A9/A9 genotype of the SLC6A3 40 bp-VNTR are involved in the vulnerability to AD in the population studied. However, for the DRD2/ANKK1 SNP does not present contributions to the development of AD.

Excessive disgust caused by brain lesions or temporary inactivations: mapping hotspots of the nucleus accumbens and ventral pallidum.

Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense 'disgust reactions' (e.g. gapes) to a normally pleasant sensation such as sweetness. Here, we aimed to map forebrain candidates more precisely, to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol/baclofen microinjections) caused rats to show excessive sensory disgust reactions to sucrose. Our study compared subregions of the nucleus accumbens shell, ventral pallidum, lateral hypothalamus, and adjacent extended amygdala. The results indicated that the posterior half of the ventral pallidum was the only forebrain site where intense sensory disgust gapes in response to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness 'liking'). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust, but lesions never did at any site. Furthermore, even inactivations failed to induce disgust in the rostral half of the accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior and rostral halves of the medial shell.

Interactive effects of chronic cigarette smoking and age on brain volumes in controls and alcohol-dependent individuals in early abstinence.

Chronic alcohol-use disorders (AUDs) have been shown to interact with normal age-related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly co-morbid condition in AUD and its influence on age-related brain atrophy have not been evaluated. We performed 1.5 T quantitative magnetic resonance imaging in non-smoking controls [non-smoking light drinking controls (nsCONs); n = 54], smoking light drinking controls (sCONs, n = 34), and one-week abstinent, treatment-seeking alcohol-dependent (ALC) non-smokers (nsALCs, n = 35) and smokers (sALCs, n = 43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS). The nsCONs and sALCs showed greater age-related volume losses than the nsALCs in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. The nsALCs and sALCs demonstrated smaller volumes than the nsCONs in most cortical region of interests (ROIs). The sCONs had smaller volumes than the nsCONs in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. The nsALCs and sALCs had smaller volumes than the sCONs in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between the nsALCs and sALCs were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in the sCONs and sALCs. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD.

Endogenous opioids in the olfactory tubercle and their roles in olfaction and quality of life.

Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.

Loss in connectivity among regions of the brain reward system in alcohol dependence.

A recently developed measure of structural brain connectivity disruption, the loss in connectivity (LoCo), is adapted for studies in alcohol dependence. LoCo uses independent tractography information from young healthy controls to project the location of white matter (WM) microstructure abnormalities in alcohol-dependent versus nondependent individuals onto connected gray matter (GM) regions. LoCo scores are computed from WM abnormality masks derived at two levels: (1) groupwise differences of alcohol-dependent individuals (ALC) versus light-drinking (LD) controls and (2) differences of each ALC individual versus the LD control group. LoCo scores based on groupwise WM differences show that GM regions belonging to the extended brain reward system (BRS) network have significantly higher LoCo (i.e., disconnectivity) than those not in this network (t = 2.18, P = 0.016). LoCo scores based on individuals' WM differences are also higher in BRS versus non-BRS (t = 5.26, P = 3.92 × 10(-6) ) of ALC. These results suggest that WM alterations in alcohol dependence, although subtle and spatially heterogeneous across the population, are nonetheless preferentially localized to the BRS. LoCo is shown to provide a more sensitive estimate of GM involvement than conventional volumetric GM measures by better differentiating between brains of ALC and LD controls (rates of 89.3% vs. 69.6%). However, just as volumetric measures, LoCo is not significantly correlated with standard metrics of drinking severity. LoCo is a sensitive WM measure of regional cortical disconnectivity that uniquely characterizes anatomical network disruptions in alcohol dependence.

Elucidation of the mechanisms of exercise-induced hypoalgesia and pain prolongation due to physical stress and the restriction of movement.

Persistent pain signals cause brain dysfunction and can further prolong pain. In addition, the physical restriction of movement (e.g., by a cast) can cause stress and prolong pain. Recently, it has been recognized that exercise therapy including rehabilitation is effective for alleviating chronic pain. On the other hand, physical stress and the restriction of movement can prolong pain. In this review, we discuss the neural circuits involved in the control of pain prolongation and the mechanisms of exercise-induced hypoalgesia (EIH). We also discuss the importance of the mesolimbic dopaminergic network in these phenomena.

Premorbid Personality Traits as Risk Factors for Behavioral Addictions: A Systematic Review of a Vulnerability Hypothesis.

The debate on personality structure and behavioral addictions is an outstanding issue. According to some authors, behavioral addictions could arise from a premorbid personality, while for others, it could result from a pathological use of technological tools. The current study aims to investigate whether, in the latest literature, personality traits have been identified as predictors of behavioral addictions. A literature search was conducted under the PRISMA methodology, considering the most relevant studies of the five-factor model from the past 10 years. Overall, most studies on addiction, personality traits, and personality genetics proved that behavioral addiction may be an epiphenomenon of a pre-existing personality structure, and that it more easily occurs in vulnerable subjects with emotional instability, negative affects, and unsatisfactory relationships with themselves, others, and events. Such neurotic personality structure was common to any addictive behavior, and was the main risk factor for both substance and behavioral addictions. Therefore, in clinical and educational contexts, it becomes crucial to primarily focus on the vulnerability factors, at-risk personality traits, and protective and moderating traits such as extroversion, agreeableness, conscientiousness, and openness to experience; meanwhile, treatment of behavioral addictions is frequently focused on overt pathological behaviors.

Ultra-Processed Food, Reward System and Childhood Obesity.

Obesity and overweight are a major public health problem globally. Diet quality is critical for proper child development, and an unhealthy diet is a preventable risk factor for noncommunicable diseases (NCDs), such as obesity. Consumption of sugar-sweetened beverages and ultra-processed foods (UPFs) in childhood may increase the BMI/BMI z-score, body fat percentage, or likelihood of overweight. A strict feeding regulation system allows for sufficient food to be consumed to meet ongoing metabolic demands while avoiding overconsumption. This narrative review explores the issues of obesity and the regulation of food intake related to reward systems and UPF consumption. Nutrient composition alone cannot explain the influence of UPFs on the risk of obesity. Furthermore, the non-nutritional properties of UPFs may explain the mechanisms underlying the relationship with obesity and NCDs. UPFs are designed to be highly palatable, appealing, and energy dense with a unique combination of the main taste enhancer ingredients to generate a strong rewarding stimulus and influence the circuits related to feeding facilitation. How individual UPF ingredients influence eating behavior and reward processes remains not fully elucidated. To increase the knowledge on the relationship between UPFs and pediatric obesity, it may be useful to limit the rapid growth in the prevalence of obesity and subsequent related complications, and to develop new strategies for appropriate food and nutrition policies.