Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.

We explored the involvement of Oxytocin receptor (Oxtr)/ Transient-receptor-potential-vanilloid-1 (TRPV1) genes and Oxytocin (Oxt) on the adaptation of skeletal muscle to cold stress challenge in mice. Oxtr expression in hypothalamic paraventricular (PVN), supraoptic nuclei (SON), and hippocampus (HIPP) were evaluated by immunohistochemistry in parallel with the measurement of circulating Oxt. The Oxtr and TRPV1 gene expression in Soleus (SOL) and Tibialis Anterior (TA) muscles were investigated by RT-PCR. Histological studies of the cardiac muscle after cold stress were also performed. Male mice (n=15) were divided into controls maintained at room temperature (RT=24°C), exposed to cold stress (CS) at T=4°C for 6 hours (6h), and 5 days (5d). Immunohistochemical studies showed that Oxtr protein expression increased by 2-fold (p=0.01) in PVN and by 1.5-fold (p=0.0001) in HIPP after 6h and 5d CS, but decreased by 2-fold (p=0.026) in SON at 5d. Both Oxtr and TRPV1 gene expression increased after 6h and 5d CS in SOL and TA muscles. Oxtr vs TRPV1 gene expression in SOL and TA muscles evaluated by regression analysis was linearly correlated following CS at 6h and 5d but not at control temperature of 24+1°C, supporting the hypothesis of coupling between these genes. The circulating levels of Oxt are unaffected after 6h CS but decreased by 0.2-fold (p=0.0141) after 5d CS. This is the first report that Oxtr and TRPV1 expression are upregulated in response to cold acclimation in skeletal muscle. The up-regulation of Oxtr in PVN and HIPP balances the decrease of circulating Oxt.

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.

Neurogenesis is a complex process by which neural progenitor cells (NPCs)/neural stem cells (NSCs) proliferate and differentiate into new neurons and other brain cells. In adulthood, the hippocampus is one of the areas with more neurogenesis activity, which is involved in the modulation of both emotional and cognitive hippocampal functions. This complex process is affected by many intrinsic and extrinsic factors, including nutrition. In this regard, preclinical studies performed in rats and mice demonstrate that high fats and/or sugars diets have a negative effect on adult hippocampal neurogenesis (AHN). In contrast, diets enriched with bioactive compounds, such as polyunsaturated fatty acids and polyphenols, as well as intermittent fasting or caloric restriction, can induce AHN. Interestingly, there is also growing evidence demonstrating that offspring AHN can be affected by maternal nutrition in the perinatal period. Therefore, nutritional interventions from early stages and throughout life are a promising perspective to alleviate neurodegenerative diseases by stimulating neurogenesis. The underlying mechanisms by which nutrients and dietary factors affect AHN are still being studied. Interestingly, recent evidence suggests that additional peripheral mediators may be involved. In this sense, the microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could act as a link between nutritional factors and AHN. The aim of this mini-review is to summarize, the most recent findings related to the influence of nutrition and diet in the modulation of AHN. The importance of maternal nutrition in the AHN of the offspring and the role of the microbiota-gut-brain axis in the nutrition-neurogenesis relationship have also been included.

Obesity is a complex disorder, and the number of people affected is growing every day. In recent years, research has confirmed the hypothesis that food addiction is a determining factor in obesity. Food addiction is a behavioral disorder characterized by disruptions in the reward system in response to hedonic eating. The endocannabinoid system (ECS) plays an important role in the central and peripheral control of food intake and reward-related behaviors. Moreover, both obesity and food addiction have been linked to impairments in the ECS function in various brain regions integrating peripheral metabolic signals and modulating appetite. For these reasons, targeting the ECS could be a valid pharmacological therapy for these pathologies. However, targeting the cannabinoid receptors with inverse agonists failed when used in clinical contexts as a consequence of the induction of affective disorders. In this context, new classes of drugs acting either on CB1 and/or CB2 receptors or on synthetic and degradation enzymes of endogenous cannabinoids are being studied. However, further investigation is necessary to find safe and effective treatments that can exert anti-obesity effects, normalizing reward-related behaviors without causing important adverse mood effects.

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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.

The widespread use of added sugars or non-nutritive sweeteners in processed foods is a challenge for addressing the therapeutics of obesity and diabetes. Both types of sweeteners generate health problems, and both are being blamed for multiple complications associated with these prevalent diseases. As an example, fructose is proven to contribute to obesity and liver steatosis, while non-nutritive sweeteners generate gut dysbiosis that complicates the metabolic control exerted by the liver. The present work explores an alternative approach for sweetening through the use of a simple carob-pod-derived syrup. This sweetener consists of a balanced mixture of fructose (47%) and glucose (45%), as sweetening sugars, and a functional natural ingredient (D-Pinitol) at a concentration (3%) capable of producing active metabolic effects. The administration of this syrup to healthy volunteers (50 g of total carbohydrates) resulted in less persistent glucose excursions, a lower insulin response to the hyperglycemia produced by its ingestion, and an enhanced glucagon/insulin ratio, compared to that observed after the ingestion of 50 g of glucose. Daily administration of the syrup to Wistar rats for 10 days lowered fat depots in the liver, reduced liver glycogen, promoted fat oxidation, and was devoid of toxic effects. In addition, this repeated administration of the syrup improved glucose handling after a glucose (2 g/kg) load. Overall, this alternative functional sweetener retains the natural palatability of a glucose/fructose syrup while displaying beneficial metabolic effects that might serve to protect against the progression towards complicated obesity, especially the development of liver steatosis.