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5-HT1A receptor (5-HT1A-R) is a serotoninergic G-protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5-HT-R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure-activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5-HT1A-R selective/preferential ligands; (ii) identification of 5-HT1A-R biased agonists, differentiating pre- versus post-synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well-defined poly-pharmacological profiles targeting 5-HT1A-R along with other serotonin receptors, serotonin transporter (SERT), D2-like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5-HT1A-R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017-2023) have been discussed. The development of chemical and pharmacological 5-HT1A-R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5-HT1A-R and the therapeutic potential of ligands targeting this receptor have been considered., (© 2024 Wiley Periodicals LLC.)

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 A 2A receptor (A 2A AR) 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 A 2A AR 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 A 2A AR and in the amygdala and caudate putamen for D2R., Discussion: The alterations on A 2A AR 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 A 2A receptor (A 2A AR) 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., (© 2024 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Objective: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge-eating disorder (BED) and study its dose-response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin-A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge-eating phenotype in the rat model used., Method: Binge-like eating of highly palatable food (HPF) in rats was induced through priming by intermittent, repeated periods of dieting and access to HPF, followed by an additional challenge with acute stress. Effects of nivasorexant were compared to the SO1RAs ACT-335827 and IDOR-1104-2408. OXA expression in neurons and neuronal fibers as well as ΔFosB and OXA-ΔFosB co-expression was studied in relevant brain regions using immuno- or immunofluorescent histochemistry., Results: All SO1RAs dose-dependently reduced binge-like eating with effect sizes comparable to the positive control topiramate, at unbound drug concentrations selectively blocking brain OX1Rs. Nivasorexant's efficacy was maintained upon chronic dosing and under conditions involving more frequent stress exposure. Priming for binge-like eating or nivasorexant treatment resulted in only minor changes in OXA or ΔFosB expression in few brain areas., Discussion: Selective OX1R blockade reduced binge-like eating in rats. Neither ΔFosB nor OXA expression proved to be a useful classifier for their binge-eating phenotype. The current results formed the basis for a clinical phase II trial in BED, in which nivasorexant was unfortunately not efficacious compared with placebo., Public Significance: Nivasorexant is a new investigational drug for the treatment of binge-eating disorder (BED). It underwent clinical testing in a phase II proof of concept trial in humans but was not efficacious compared with placebo. The current manuscript investigated the drug's efficacy in reducing binge-like eating behavior of a highly palatable sweet and fat diet in a rat model of BED, which initially laid the foundation for the clinical trial., (© 2024 Idorsia Pharmaceuticals Ltd and The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Rationale: In 2018, the International Classification of Diseases (ICD-11) classified Gaming Disorder (GD) as a mental disorder. GD mainly occurs among adolescents, who, after developing addiction, show psychopathological traits, such as social anxiety, depression, social isolation, and attention deficit. However, the different studies conducted in humans so far show several limitations, such as the lack of demographic heterogeneity and equal representation of age, differences in the type of game and in the follow-up period. Furthermore, at present, no animal models specific to GD are available., Objectives: To address the lack of an experimental model for GD, in the present work, we proposed a new GD rat model to investigate some peculiar tracts of the disorder., Methods: Two-month-old Wistar Kyoto rats, both males and females, were subject to a five-week training with a new innovative touch-screen platform. After five weeks of training, rats were assessed for: (a) their attachment to the play under several conditions, (b) their hyperactivity during gaming, and (c) the maintenance of these conditions after a period of game pause and reward interruption. After sacrifice, using immunohistochemistry techniques, the immunoreactivity of c-Fos (a marker of neuronal activity) was analyzed to study different neural areas., Results: After the training, the rats subjected to GD protocol developed GD-related traits (e.g., hyperactivity, loss control), and the behavioral phenotype was maintained consistently over time. These aspects were completely absent in the control groups. Lastly, the analysis of c-Fos immunoreactivity in prelimbic cortex (PrL), orbitofrontal cortex (OFC), nucleus Accumbens, amygdala and bed nucleus of stria terminalis (BNST) highlighted significant alterations in the GD groups compared to controls, suggesting modifications in neural activity related to the development of the GD phenotype., Conclusions: The proposal of a new GD rat model could represent an innovative tool to investigate, in both sexes, the behavioral and neurobiological features of this disorder, the possible role of external factors in the predisposition and susceptibility and the development of new pharmacological therapies., (© 2024. The Author(s).)

Obesity has a great impact on adipose tissue biology, based on its function as a master regulator of energy balance. Brown adipose tissue (BAT) undergoes remodeling, and its activity declines in obese subjects due to a whitening process. The anti-obesity properties of fruit extracts have been reported. The effects of tart cherry against oxidative stress, inflammation, and the whitening process in the BAT of obese rats were investigated. Intrascapular BAT (iBAT) alterations and effects of Prunus cerasus L. were debated in rats fed for 17 weeks with a high-fat diet (DIO), in DIO supplemented with seed powder (DS), and with seed powder plus the juice (DJS) of tart cherry compared to CHOW rats fed with a normo-caloric diet. iBAT histologic observations revealed a whitening process in DIO rats that was reduced in the DS and DJS groups. A modulation of uncoupling protein-1 (UCP-1) protein and gene expression specifically were detected in the obese phenotype. An upregulation of UCP-1 and related thermogenic genes after tart cherry intake was detected compared to the DIO group. Metabolic adjustment, endoplasmic reticulum stress, protein carbonylation, and the inflammatory microenvironment in the iBAT were reported in DIO rats. The analysis demonstrated an iBAT modulation that tart cherry promoted. In addition to our previous results, these data confirm the protective impact of tart cherry consumption on obesity.

Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered., (© 2023 Wiley Periodicals LLC.)

Neuromedin U (NMU) is a bioactive peptide produced in the gut and in the brain, with a role in multiple physiological processes. NMU acts by binding and activating two G protein coupled receptors (GPCR), the NMU receptor 1 (NMU-R1), which is predominantly expressed in the periphery, and the NMU receptor 2 (NMU-R2), mainly expressed in the central nervous system (CNS). In the brain, NMU and NMU-R2 are consistently present in the hypothalamus, commonly recognized as the main "feeding center". Considering its distribution pattern, NMU revealed to be an important neuropeptide involved in the regulation of food intake, with a powerful anorexigenic ability. This has been observed through direct administration of NMU and by studies using genetically modified animals, which revealed an obesity phenotype when the NMU gene is deleted. Thus, the development of NMU analogs or NMU-R2 agonists might represent a promising pharmacological strategy to treat obese individuals. Furthermore, NMU has been demonstrated to influence the non-homeostatic aspect of food intake, playing a potential role in binge eating behavior. This review aims to discuss and summarize the current literature linking the NMU system with obesity and binge eating behavior, focusing on the influence of NMU on food intake and the neuronal mechanisms underlying its anti-obesity properties. Pharmacological strategies to improve the pharmacokinetic profile of NMU will also be reported., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest associated with the content of this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Consumption of energy-dense palatable "comfort" food can alleviate stress and negative emotions, while abrupt withdrawal from a palatable diet can worsen these symptoms, causing difficulties with adherence to weight-loss diets. Currently, no pharmacological treatment is effective for obesity-related anxiety, so we investigated the endocannabinoid system (ECS), and specifically the fatty acid amide hydrolase (FAAH), as an interesting emerging target in this context because of its key role in the regulation of both energy homeostasis and emotional behavior., Methods: Rats were subjected to exposure and subsequent abstinence from a palatable cafeteria diet. During abstinence period, rats were treated with the selective FAAH inhibitor PF-3845 (10 mg/kg; intraperitoneal administration every other day)., Results: Abstinent rats displayed an anxiogenic-like behavior and changes in the proteins of ECS signaling machinery in brain areas involved both in anxiety and food intake regulation. In particular, withdrawal caused a reduction of the expression of cannabinoid receptors in the nucleus accumbens and of enzymes diacylglycerol lipase alpha and monoacylglycerol lipase (MAGL) in the amygdala. Pharmacological inhibition of FAAH exerted an anxiolytic-like effect in abstinent animals and increased both MAGL expression in amygdala and CB2 expression in prefrontal cortex., Discussion: Overall, our results suggest that emotional disturbances associated with dieting are coupled with region-specific alterations in the cerebral expression of the ECS and that the enhancement of the endocannabinoid signaling by FAAH inhibition might represent a novel pharmacological strategy for the treatment of anxiety related to abstinence from palatable food., Public Significance: The present study focused on evaluating the role of the endocannabinoid system in modulating withdrawal from naturally rewarding activities that have an impact on mood, such as feeding. The variations observed in the emotional behavior of abstinent rats was linked to neuroadaptations of the ECS in specific brain areas., (© 2023 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

The irregular lifestyle of airline crew members, wide/adverse job-related exposures, and the impact of temporary hypoxia on gut microbiota well-being have increased concern about the daily recommended dose of certain nutrients among flight crew. The aim of this study was to determine if daily consumption of a SYNBIO ® probiotics-elderberry extract supplement (ACTIVE) may contribute to the well-being of flight attendants. Forty healthy crew members enrolled in a double-blind, randomized, placebo-controlled study consumed one ACTIVE capsule/day or placebo for 30 days. Bowel well-being, health-related quality of life, and gastrointestinal tolerance were assessed by validated questionnaires. Saliva and fecal samples were analyzed to determine secretory immunoglobulin-A (sIgA) levels and to characterize gut microbiota composition, respectively. ACTIVE subjects presented a physiological improvement and a statistically significant higher Psychological General Well-Being Index (PGWBI) global score compared to PLACEBO subjects. The ACTIVE subjects showed significantly increased levels of lactobacilli and bifidobacteria compared to the PLACEBO group, while a significant increase in lactobacilli and a significant reduction in Enterobacteriaceae were registered when compared with the beginning of supplementation, confirming the persistence of probiotics in the gastrointestinal tract and the direct antagonism and competitive exclusion effects. Additionally, sIgA levels were significantly higher in the ACTIVE group compared to the baseline and to the PLACEBO group at the end of supplementation. The ACTIVE supplementation might be beneficial to airline crew members, improving their physiological state, their immune defenses, and the strength and efficiency of their gastrointestinal tract when responding to stressful conditions.

The physiological changes associated with ageing contribute to the incidence of diseases, morbidity, and mortality. For modern society, it is essential to find solutions to improve elderly people's health and quality of life. Among promising strategies, the PROBIOSENIOR project proposed a daily six-month supplementation with new probiotic functional foods and nutraceuticals. The aim of this work was to evaluate the modulating effects of the probiotic diet on inflammatory markers and nutritional status. Ninety-seven elderly volunteers were randomly assigned to either a placebo-diet group or a probiotic-diet group (SYNBIO ® ). Faeces, urine, and blood samples were collected before and after the supplementation to determine serum cytokines, biogenic amines, and inflammation markers. Comparing the results obtained before and after the intervention, probiotic supplementations significantly decreased the TNF-α circulating levels and significantly increased those of IGF-1. Biogenic-amine levels showed high variability, with significant variation only for histamine that decreased after the probiotic supplementation. The supplementation influenced the serum concentration of some crucial cytokines (IL-6, IL-8, and MIP-1α) that significantly decreased in the probiotic group. In addition, the Mini Nutritional Assessment questionnaire revealed that the probiotic-supplemented group had a significant improvement in nutritional status. In conclusion, the PROBIOSENIOR project demonstrated how SYNBIO ® supplementation may positively influence some nutritional and inflammatory parameters in the elderly.

Recurrent Binge Eating (BE) episodes characterize several eating disorders. Here, we attempted to reassemble a condition closer to BE disorder, and we analyzed whether recurrent episodes might evoke molecular alterations in the hypothalamus of rats. The hypothalamus is a brain region which is sensitive to stress and relevant in motivated behaviors, such as food intake. A well-characterized animal model of BE, in which a history of intermittent food restriction and stress induce binge-like palatable food consumption, was used to analyze the transcriptional regulation of the endocannabinoid system (ECS). We detected, in rats showing the BE behavior, an up-regulated gene expression of cannabinoid type-1 receptor (CB1), sn-1-specific diacylglycerol lipase, as well as fatty acid amide hydrolase ( Faah ) and monoacylglycerol lipase. A selective reduction in DNA methylation was also observed at the promoter of Faah , which is consistent with the changes in the gene expression. Moreover, BE behavior in rats was associated with an increase in anandamide (AEA) levels. Our findings support the relevant role of the ECS in the regulation of food intake in rats subjected to repeated BE episodes, and, in particular, on AEA signaling, acting via CB1 and FAAH modulation. Notably, the epigenetic regulation of the Faah gene might suggest this enzyme as a possible target for developing new therapeutical approaches., Competing Interests: The authors declare no conflicts of interest.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress., Competing Interests: Conflict of interest All authors declare that there are no conflicts of interest associated with the content of this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Probiotic supplementation approach offers the possibility to shape the gut microbiota (GM), enabling the development of innovative formulations able to improve intestinal well-being and consequently the related body weight modulation and energy metabolism. In the present clinical study, a new potential probiotic supplement based on Lactiplantibacillus plantarum IMC 510 was studied for weight management., Methods and Results: Quantitative characterization by qPCR of representative bacterial groups of GM was used to determine the microbiota modulation at different supplementation periods. Furthermore, measurement of the endpoints linked to weight control (body mass index, body weight, waist circumference) was assessed. Specific questionnaires to evaluate the impact on psychological and physiological point of view were performed. Results showed that after 90 days, Lact. plantarum IMC 510 supplementation brought an improvement in endpoints linked to weight control and healthy status, although no significant changes in the microbiota composition were reported for analysed bacterial groups, except for Lactobacillus spp. and Bifidobacterium spp., Conclusions: We concluded that Lact. plantarum IMC 510 supplementation could be an interesting tool for weight management. More studies are needed to understand the impact on GM, for example, evaluating the production of short-chain fatty acids, since their important role in dietary metabolism. Further research is necessary to better elucidate the relationship between GM and overweight and the mechanism of action by which Lact. plantarum IMC 510 modifies body weight., Significance and Impact of the Study: However, these promising outcomes represent a clear advantage of probiotic supplementation and identify a new potential probiotic as a novel and safe therapeutic approach in the obesity prevention and management., (© 2022 Society for Applied Microbiology.)

The neuropeptide S (NPS) is the endogenous ligand of the NPS receptor (NPSR). The NPSR is widely expressed in brain regions that process emotional and affective behavior. NPS possesses a unique physio-pharmacological profile, being anxiolytic and promoting arousal at the same time. Intracerebroventricular NPS decreased alcohol consumption in alcohol-preferring rats with no effect in non-preferring control animals. This outcome is most probably linked to the anxiolytic properties of NPS, since alcohol preference is often associated with high levels of basal anxiety and intense stress-reactivity. In addition, NPSR mRNA was overexpressed during ethanol withdrawal and the anxiolytic-like effects of NPS were increased in rodents with a history of alcohol dependence. In line with these preclinical findings, a polymorphism of the NPSR gene was associated with anxiety traits contributing to alcohol use disorders in humans. NPS also potentiated the reinstatement of cocaine and ethanol seeking induced by drug-paired environmental stimuli and the blockade of NPSR reduced reinstatement of cocaine-seeking. Altogether, the work conducted so far indicates the NPS/NPSR system as a potential target to develop new treatments for alcohol and cocaine abuse. An NPSR agonist would be indicated to help individuals to quit alcohol consumption and to alleviate withdrawal syndrome, while NPSR antagonists would be indicated to prevent relapse to alcohol- and cocaine-seeking behavior.

Introduction: During the 2019 Coronavirus pandemic (COVID-19), a concern emerged regarding a possible correlation between the severe form of SARS-CoV-2 infection and administration of ACE-Inhibitors (ACE-I) and Sartans (ARB), since long-term use of these drugs may potentially result in an adaptive response with up-regulation of the ACE 2 receptor. Given the crucial role of ACE2, being the main target for virus entry into the cell, the potential consequences of ACE2 up-regulation have been a source of debate. The aim of this retrospective cohort study on COVID-19-positive patients who died is to investigate whether previous long-term exposure to ACE-I and/or ARB was associated with higher mortality due to COVID-19 infection, compared to all other types of drug treatment., Methods: We analysed the clinical and demographic data of 615 patients hospitalized for COVID-19 at the two hospitals of the Vasta Area n.5, between March 2020 and April 2021. Among them, 86 patients, treated with ACE-Is and/0 ARBs for about 12 months, died during hospitalization following a diagnosis of acute respiratory failure. Several quantitative and qualitative variables were recorded for all patients by reading their medical records., Results: The logistic model showed that the variables that increase mortality are age and comorbid diseases. There were no demonstrable mortality effects with ACE-I and ARB intake., Conclusions: The apparent increase in morbidity in patients with COVID-19 who received long-term treatment with ACE-I or ARB is not due to the drugs themselves, but to the conditions associated with their use.

Obesity is a risk factor for cardiovascular diseases, frequently related to oxidative stress and inflammation. Dietary antioxidant compounds improve heart health. Here, we estimate the oxidative grade and inflammation in the heart of dietary-induced obese (DIO) rats after exposure to a high-fat diet compared to a standard diet. The effects of tart cherry seed powder and seed powder plus tart cherries juice were explored. Morphological analysis and protein expressions were performed in the heart. The oxidative status was assessed by the measurement of protein oxidation and 4-hydroxynonenal in samples. Immunochemical and Western blot assays were performed to elucidate the involved inflammatory markers as proinflammatory cytokines and cellular adhesion molecules. In the obese rats, cardiomyocyte hypertrophy was accompanied by an increase in oxidative state proteins and lipid peroxidation. However, the intake of tart cherries significantly changed these parameters. An anti-inflammatory effect was raised from tart cherry consumption, as shown by the downregulation of analyzed endothelial cell adhesion molecules and cytokines compared to controls. Tart cherry intake should be recommended as a dietary supplement to prevent or counteract heart injury in obese conditions.

A link between obesity and cerebral health is receiving growing recognition. Here, we investigate in the frontal cortex and hippocampus the potential involvement of cholinergic markers in brain alterations previously reported in rats with obesity induced by diet (DIO) after long-term exposure (17 weeks) to a high-fat diet (HFD) in comparison with animals fed with a standard diet (CHOW). The obesity developed after 5 weeks of HFD. Bodyweight, systolic blood pressure, glycemia, and insulin levels were increased in DIO rats compared to the CHOW group. Measurements of malondialdehyde (MDA) provided lipid peroxidation in HFD-fed rats. Western blot and immunohistochemical techniques were performed. Our results showed a higher expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in obese rats but not the VAChT expression in the frontal cortex after 17 weeks of HFD. Furthermore, the acetylcholinesterase (AChE) enzyme was downregulated in HFD both in the frontal cortex and hippocampus. In the brain regions analyzed, it was reported a modulation of certain cholinergic receptors expressed pre- and post-synaptically (alpha7 nicotinic receptor and muscarinic receptor subtype 1). Collectively, these findings point out precise changes of cholinergic markers that can be targeted to prevent cerebral injuries related to obesity.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety.

Evidence suggests that transient receptor potential (TRP) ion channels dysfunction significantly contributes to the physiopathology of metabolic and neurological disorders. Dysregulation in functions and expression in genes encoding the TRP channels cause several inherited diseases in humans (the so-called 'TRP channelopathies'), which affect the cardiovascular, renal, skeletal, and nervous systems. This study aimed to evaluate the expression of ion channels in the forebrain of rats with diet-induced obesity (DIO). DIO rats were studied after 17 weeks under a hypercaloric diet (high-fat diet, HFD) and were compared to the control rats with a standard diet (CHOW). To determine the systemic effects of HFD exposure, we examined food intake, fat mass content, fasting glycemia, insulin levels, cholesterol, and triglycerides. qRT-PCR, Western blot, and immunochemistry analysis were performed in the frontal cortex (FC) and hippocampus (HIP). After 17 weeks of HFD, DIO rats increased their body weight significantly compared to the CHOW rats. In DIO rats, TRPC1 and TRPC6 were upregulated in the HIP, while they were downregulated in the FC. In the case of TRPM2 expression, instead was increased both in the HIP and in the FC. These could be related to the increase of proteins and nucleic acid oxidation. TRPV1 and TRPV2 gene expression showed no differences both in the FC and HIP. In general, qRT-PCR analyses were confirmed by Western blot analysis. Immunohistochemical procedures highlighted the expression of the channels in the cell body of neurons and axons, particularly for the TRPC1 and TRPC6. The alterations of TRP channel expression could be related to the activation of glial cells or the neurodegenerative process presented in the brain of the DIO rat highlighted with post synaptic protein (PSD 95) alterations. The availability of suitable animal models may be useful for studying possible pharmacological treatments to counter obesity-induced brain injury. The identified changes in DIO rats may represent the first insight to characterize the neuronal alterations occurring in obesity. Further investigations are necessary to characterize the role of TRP channels in the regulation of synaptic plasticity and obesity-related cognitive decline.

Changes in functionality and composition of gut microbiota (GM) have been associated and may contribute to the development and maintenance of obesity and related diseases. The aim of our study was to investigate for the first time the impact of Lactiplantibacillus (L.) plantarum IMC 510 in a rat model of diet-induced obesity, specifically in the cafeteria (CAF) diet. This diet provides a strong motivation to voluntary overeat, due to the palatability and variety of selected energy-dense foods. The oral administration for 84 days of this probiotic strain, added to the CAF diet, decreased food intake and body weight gain. Accordingly, it ameliorated body mass index, liver and white adipose tissue weight, hepatic lipid accumulation, adipocyte size, serum parameters, including glycemia and low-density lipoprotein levels, in CAF fed rats, potentially through leptin control. In this scenario, L. plantarum IMC 510 showed also beneficial effects on GM, limiting the microbial imbalance established by long exposure to CAF diet and preserving the proportion of different bacterial taxa. Further research is necessary to better elucidate the relationship between GM and overweight and then the mechanism of action by which L. plantarum IMC 510 modifies weight. However, these promising results prompt a clear advantage of probiotic supplementation and identify a new potential probiotic as a novel and safe therapeutic approach in obesity prevention and management.

The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin's functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic-pituitary-adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: There is increasing evidence for the involvement of dietary bioactive compounds in the cross-talk modulation of endocannabinoid system and some of the key regulators of transcriptional control for adipogenesis., Methods: We aimed to characterize the expression of cannabinoid CB1/CB2 receptors and fatty acid amide hydrolase (FAAH) along with selected adipogenesis-related genes (PPARγ, SREBP-1c and PREF-1), adipocyte-secreted factors (leptin and adiponectin), mitochondrial bioenergetic modulators (PGC-1A and UCP-2), and transient receptor potential vanilloid subtype 1 (TRPV1) and 2 (TRPV2) channels in visceral adipose tissue of rats fed with a high-fat diet (HFD) containing either tart cherry seeds alone or tart cherry seeds and juice for 17 weeks. The visceral adipose tissue was weighed and checked the expression of different markers by qRT-PCR, Western blot and immunohistochemistry., Results: Tart cherry supplements were able to downregulate the HFD-induced mRNA expression of CB1 receptor, SREBP-1c, PPARγ, leptin, TRPV1 and TRPV2 resulting in potential anti-adipogenic effects., Conclusion: The present study points out that the intake of bioactive constituents of tart cherry may attenuate the effect of adipogenesis by acting directly on the adipose tissue and modulating the interplay between CB1, PPARγ and TRPV channel gene transcription., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Obesity represents one of the most important challenges in the contemporary world that must be overcome. Different pathological consequences of these physical conditions have been studied for more than 30 years. The most nagging effects were found early in the cardiovascular system. However, later, its negative impact was also investigated in several other organs. Damage at cellular structures due to overexpression of reactive oxygen species together with mechanisms that cause under-production of antioxidants leads to the development of obesity-related complications. In this view, the negative results of oxidant molecules due to obesity were studied in various districts of the body. In the last ten years, scientific literature has reported reasonable evidence regarding natural and synthetic compounds' supplementation, which showed benefits in reducing oxidative stress and inflammatory processes in animal models of obesity. This article attempts to clarify the role of oxidative stress due to obesity and the opposing role of antioxidants to counter it, reported in preclinical studies. This analysis aims to clear-up different mechanisms that lead to the build-up of pro-oxidants during obesity and how various molecules of different origins hinder this phenomenon, behaving as antioxidants.

Maladaptive eating behavior is a growing public health problem and compulsively eating excessive food in a short time, or binge eating, is a key symptom of many eating disorders. In order to investigate the binge-like eating behavior in female rats, induced by intermittent food restrictions/refeeding and frustration stress, we analyzed for the first time the metabolic profile obtained from serum of rats, through nuclear magnetic resonance (NMR) spectroscopy. In this experimental protocol, rats were exposed to chow food restricting/refeeding and frustration stress manipulation. This stress procedure consists of 15 min exposure to the odor and sight of a familiar chocolate paste, without access to it, just before offering the palatable food. In this model, a "binge-eating episode" was considered the significantly higher palatable food consumption within 2 h in restricted and stressed rats (R + S) than in the other three experimental groups: rats with no food restriction and no stress (NR + NS), only stressed rats (NR + S) or only restricted rats (R + NS). Serum samples from these four different rat groups were collected. The statistical analysis of the 1 H NMR spectral profiles of the four sets of samples pointed to O- and N-acetyl glycoproteins as the main biomarkers for the discrimination of restriction effects. Other metabolites, such as threonine, glycine, glutamine, acetate, pyruvate and lactate, showed trends that may be useful to understand metabolic pathways involved in eating disorders. This study suggested that NMR-based metabolomics is a suitable approach to detect biomarkers related to binge-eating behavior., (© 2021 John Wiley & Sons, Ltd.)

The Neuropeptide S (NPS), a 20 amino acids peptide, is recognized as the endogenous ligand of a previously orphan G protein-coupled receptor, now termed NPS receptor (NPSR). The limited distribution of the NPS-expressing neurons in few regions of the brainstem is in contrast with the extensive expression of NPSR in the rodent central nervous system, suggesting the involvement of this receptor in several brain functions. In particular, NPS promotes locomotor activity, behavioral arousal, wakefulness, and unexpectedly, at the same time, it exerts anxiolytic-like properties. Intriguingly, the NPS system is implicated in the rewarding properties of drugs of abuse and in the regulation of food intake. Here, we focus on the anorexigenic effect of NPS, centrally injected in different brain areas, in both sated and fasted animals, fed with standard or palatable food, and, in addition, on its influence in the gastrointestinal tract. Further investigations, regarding the role of the NPS/NPSR system and its potential interaction with other neurotransmitters could be useful to understand the mechanisms underlying its action and to develop novel pharmacological tools for the treatment of aberrant feeding patterns and obesity.

Background: Tart cherries ( Prunus cerasus L.) are a rich source of anthocyanins. They are phytochemical flavonoids found in red and blue fruits, and vegetables that can reduce hyperlipidemia. Visceral Adipose Tissue (VAT) has emerged as a major player in driving obesity-related inflammatory response., Methods: This study has investigated the potential positive effects of tart cherries on rats with Diet-Induced Obesity (DIO). In particular, the inflammatory status in retroperitoneal (RPW) and perigonadal (PGW) adipose tissue were studied. Rats were fed ad libitum for 17 weeks with a hypercaloric diet with the supplementation of tart cherries seeds powder (DS) and seeds powder plus tart cherries juice containing 1mg of anthocyanins (DJS). In RPW and PGW, expression of CRP, IL-1 β, TNF-α, CCL2 and CD36, were measured by qRT-PCR, Western blot and immunohistochemistry techniques., Results: No differences in the weight of RPW and PGW animals were found between DS and DJS groups compared to DIO rats. However, an increase of inflammatory markers was observed in DIO group in comparison with control lean rats. A modulation of these markers was evident upon tart cherry supplementation., Conclusion: Study results suggest that tart cherry enriched-diet did not modify the accumulation of visceral fat, but it decreased inflammatory markers in both tissues. Therefore, this supplementation could be useful, in combination with healthy lifestyles, to modify adipose tissue cell metabolism limiting-obesity related organ damage.

Since its discovery, the dopamine D 4 receptor (D 4 R) has been suggested to be an attractive target for the treatment of neuropsychiatric diseases. Novel findings have renewed the interest in such a receptor as an emerging target for the management of different diseases, including cancer, Parkinson's disease, alcohol or substance use disorders, eating disorders, erectile dysfunction and cognitive deficits. The recently resolved crystal structures of D 4 R in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the D 4 R functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective D 4 R ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or β-arrestin recruitment and the effects of selective D 4 R ligands on the above-mentioned diseases are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.

The dysfunction of melanocortin signaling has been associated with obesity, given the important role in the regulation of energy homeostasis, food intake, satiety and body weight. In the hypothalamus, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) contribute to the stability of these processes, but MC3R and MC4R are also localized in the mesolimbic dopamine system, the region that responds to the reinforcing properties of highly palatable food (HPF) and where these two receptors seem to affect food reward and motivation. Loss of function of the MC4R, resulting from genetic mutations, leads to overeating in humans, but to date, a clear understanding of the underlying mechanisms and behaviors that promote overconsumption of caloric foods remains unknown. Moreover, the MC4R demonstrated to be a crucial modulator of the stress response, factor that is known to be strictly related to binge eating behavior. In this review, we will explore the preclinical and clinical studies, and the controversies regarding the involvement of melanocortin system in altered eating patterns, especially binge eating behavior, food reward and motivation.

In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ 1 ) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3 . To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at the σ 1 receptor significantly higher than that of the lead compound 1 . In particular, 3 displayed unprecedented selectivity over the σ 2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over the dopamine transporter. Docking results supported the structure-activity relationship studies. Due to its interesting biological profile, derivative 3 , selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of the σ 1 receptor in the compulsive-like eating behavior and supported the σ 1 receptor as a promising target for the management of eating disorders.

Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell ("frustration stress"). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg -1 ) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.

The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This review is focused on the role of DRD4 and DRD4 genetic polymorphism in these neuropsychiatric disorders in both clinical and preclinical studies. However, further research is needed to better clarify the complex DRD4 role, by using validated preclinical models and novel compounds more selective for DRD4.

Binge-eating disorder is the most common eating disorder. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3 (RLN3), which stimulates food intake in rats through the activation of the relaxin-family peptide-3 receptor (RXFP3). Here we demonstrate that a likely mechanism underlying the orexigenic action of RLN3 is RXFP3-mediated inhibition of oxytocin- and arginine-vasopressin-synthesizing paraventricular nucleus (PVN) magnocellular neurosecretory cells. Moreover, we reveal that, in male and female rats, this action depends on M-like potassium conductance. Notably, higher intra- and peri-PVN RLN3 fiber densities were observed in females, which may constitute an anatomic substrate for observed sex differences in binge-eating disorder. Finally, in a model of binge-eating in female rats, RXFP3 blockade within the PVN prevented binge-eating behavior. These data demonstrate a direct RLN3/RXFP3 action in the PVN of male and female rats, identify the associated ionic mechanisms, and reveal that hypothalamic RLN3/RXFP3 signaling regulates binge-eating behavior. SIGNIFICANCE STATEMENT Binge-eating disorder is the most common eating disorder worldwide, affecting women twice as frequently as men. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3, which acts via the relaxin-family peptide-3 receptor (RXFP3). Using a model of binge-eating, we demonstrated that relaxin-3/RXFP3 signaling in the hypothalamic paraventricular nucleus (PVN) is necessary for the expression of binge-eating behavior in female rats. Moreover, we elucidated the neuronal mechanism of RLN3/RXFP3 signaling in PVN in male and female rats and characterized sex differences in the RLN3 innervation of the PVN. These findings increase our understanding of the brain circuits and neurotransmitters involved in binge-eating disorder pathology and identify RXFP3 as a therapeutic target for binge-like eating disorders., (Copyright © 2020 the authors.)

Numerous nutritional approaches aimed at reducing body weight have been developed as a strategy to reduce obesity. Most of these interventions rely on reducing caloric intake or limiting calories access to a few hours per day. In this work, we analyzed the effects of the extended (24 hours/day) or restricted (1 hour/day) access to a cafeteria-style (CAF) diet, on rat body weight and hepatic lipid metabolism, with respect to control rats (CTR) fed with a standard chow diet. The body weight gain of restricted-fed rats was not different from CTR, despite the slightly higher total caloric intake, but resulted significantly lower than extended-fed rats, which showed a CAF diet-induced obesity and a dramatically higher total caloric intake. However, both CAF-fed groups of rats showed, compared to CTR, unhealthy serum and hepatic parameters such as higher serum glucose level, lower HDL values, and increased hepatic triacylglycerol and cholesterol amount. The hepatic expression and activity of key enzymes of fatty acid synthesis, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was similarly reduced in both CAF-fed groups of rats with respect to CTR. Anyway, while in extended-fed rats this reduction was associated to a long-term mechanism involving sterol regulatory element-binding protein-1 (SREBP-1), in restricted-fed animals a short-term mechanism based on PKA and AMPK activation occurred in the liver. Furthermore, hepatic fatty acid oxidation (FAO) and oxidative stress resulted significantly increased in extended, but not in restricted-fed rats, as compared to CTR. Overall, these results demonstrate that although limiting the total caloric intake might successfully fight obesity development, the nutritional content of the diet is the major determinant for the health status., (© 2020 Federation of American Societies for Experimental Biology.)

Metabolic syndrome (MetS) is an association between obesity, dyslipidemia, hyperglycemia, hypertension, and insulin resistance. A relationship between MetS and vascular dementia was hypothesized. The purpose of this work is to investigate brain microanatomy alterations in obese Zucker rats (OZRs), as a model of MetS, compared to their counterparts lean Zucker rats (LZRs). 12-, 16-, and 20-weeks-old male OZRs and LZRs were studied. General physiological parameters and blood values were measured. Immunochemical and immunohistochemical techniques were applied to analyze the brain alterations. The morphology of nerve cells and axons, astrocytes and microglia were investigated. The blood-brain barrier (BBB) changes occurring in OZRs were assessed as well using aquaporin-4 (AQP4) and glucose transporter protein-1 (GLUT1) as markers. Body weight gain, hypertension, hyperglycemia, and hyperlipidemia were found in OZRs compared to LZRs. In the frontal cortex and hippocampus, a decrease of neurons was noticeable in the older obese rats in comparison to their age-matched lean counterparts. In OZRs, a reduction of neurofilament immunoreaction and gliosis was observed. The BBB of older OZRs revealed an increased expression of AQP4 likely related to the development of edema. A down-regulation of GLUT1 was found in OZRs of 12 weeks of age, whereas it increased in older OZRs. The behavioral analysis revealed cognitive alterations in 20-week-old OZRs. Based on these results, the OZRs may be useful for understanding the mechanisms through which obesity and related metabolic alterations induce neurodegeneration.

The accumulation of adipose tissue increases the risk of several diseases. The fruits-intake, containing phytochemicals, is inversely correlated with their development. This study evaluated the effects of anthocyanin-rich tart cherries in diet-induced obese (DIO) rats. DIO rats were exposed to a high-fat diet with the supplementation of tart cherry seeds powder (DS) and seed powder plus juice (DJS). After 17 weeks, the DIO rats showed an increase of body weight, glycaemia, insulin, and systolic blood pressure. In the DS and DJS groups, there was a decrease of systolic blood pressure, glycaemia, triglycerides, and thiobarbituric reactive substances in the serum. In the DJS rats, computed tomography revealed a decrease in the spleen-to-liver attenuation ratio. Indeed, sections of the DIO rats presented hepatic injury characterized by steatosis, which was lower in the supplemented groups. In the liver of the DIO compared with rats fed with a standard diet (CHOW), a down-regulation of the GRP94 protein expression and a reduction of LC3- II/LC3-I ratio were found, indicating endoplasmic reticulum stress and impaired autophagy flux. Interestingly, tart cherry supplementation enhanced both unfolded protein response (UPR) and autophagy. This study suggests that tart cherry supplementation, although it did not reduce body weight in the DIO rats, prevented its related risk factors and liver steatosis.

Objective: Both environmental and genetic factors are known to contribute to the development of anorexia nervosa (AN), but the exact etiology remains poorly understood. Herein, we studied the transcriptional regulation of the endocannabinoid system, an interesting target for body weight maintenance and the control of food intake and energy balance., Method: We used two well-characterized animal models of AN: (a) the activity-based anorexia (ABA) model in which rats, housed with running wheels and subjected to daily food restriction, show reductions in body weight and increase in physical activity; (b) the genetic anx/anx mouse displaying the core features of AN: low food intake and emaciation., Results: Among the evaluated endocannabinoid system components, we observed a selective and significant down-regulation of the gene encoding for the type 1 cannabinoid receptor (Cnr1) in ABA rats' hypothalamus and nucleus accumbens and, in the latter area, a consistent, significant and correlated increase in DNA methylation at the gene promoter. No changes were evident in the anx/anx mice except for a down-regulation of Cnr1, in the prefrontal cortex., Discussion: Our findings support a possible role for Cnr1 in the ABA animal model of AN. In particular, its regulation in the nucleus accumbens appears to be triggered by environmental cues due to the consistent epigenetic modulation of the promoter. These data warrant further studies on Cnr1 regulation as a possible target for treatment of AN., (© 2020 Wiley Periodicals, Inc.)

There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague-Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. Ex vivo analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients., (Copyright © 2020 Cifani, Avagliano, Micioni Di Bonaventura, Giusepponi, De Caro, Cristiano, La Rana, Botticelli, Romano, Calignano, Gaetani, Micioni Di Bonaventura and Russo.)

Evidence suggests that obesity adversely affects brain function. High body mass index, hypertension, dyslipidemia, insulin resistance, and diabetes are risk factors for increasing cognitive decline. Tart cherries ( Prunus Cerasus L.) are rich in anthocyanins and components that modify lipid metabolism. This study evaluated the effects of tart cherries on the brain in diet-induced obese (DIO) rats. DIO rats were fed with a high-fat diet alone or in association with a tart cherry seeds powder (DS) and juice (DJS). DIO rats were compared to rats fed with a standard diet (CHOW). Food intake, body weight, fasting glycemia, insulin, cholesterol, and triglycerides were measured. Immunochemical and immunohistochemical techniques were performed. Results showed that body weight did not differ among the groups. Blood pressure and glycemia were decreased in both DS and DJS groups when compared to DIO rats. Immunochemical and immunohistochemical techniques demonstrated that in supplemented DIO rats, the glial fibrillary acid protein expression and microglial activation were reduced in both the hippocampus and in the frontal cortex, while the neurofilament was increased. Tart cherry intake modified aquaporin 4 and endothelial inflammatory markers. These findings indicate the potential role of this nutritional supplement in preventing obesity-related risk factors, especially neuroinflammation., Competing Interests: The authors declare no conflict of interest.

Background: Pharmacological treatment approaches for eating disorders, such as binge eating disorder and bulimia nervosa, are currently limited., Methods and Aims: Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the A 2A Adenosine Receptor (A 2A AR) and dopaminergic D2 receptor (D2R) genes., Results: Gene expression analysis revealed a selective increase of both receptor mRNAs in the amygdaloid complex of stressed and restricted rats, which exhibited binge-like eating, when compared to non-stressed and non-restricted rats. Consistently, pyrosequencing analysis revealed a significant reduction of the percentage of DNA methylation but only at the A 2A AR promoter region in rats showing binge-like behaviour compared to the control animals. Focusing thus on A 2A AR agonist (VT 7) administration (which inhibited the episode of binge systemically at 0.1 mg/kg or intra-central amygdala (CeA) injection at 900 ng/side) induced a significant increase of A 2A AR mRNA levels in restricted and stressed rats when compared to the control group. In addition, we observed a significant decrease in A 2A AR mRNA levels in rats treated with the A 2A AR antagonist (ANR 94) at 1 mg/kg. Consistent changes in the DNA methylation status of the A 2A AR promoter were found in restricted and stressed rats after administration of VT 7 or ANR 94., Conclusion: We confirm the role of A 2A AR in binge eating behaviours, and we underline the importance of epigenetic regulation of the A 2A AR gene, possibly due to a compensatory mechanism to counteract the effect of binge eating. We suggest that A 2A AR activation, inducing receptor gene up-regulation, could be relevant to reduction of food consumption.