The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue. Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue. Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies. Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in adults in developed countries, with a global prevalence as high as one billion. The pathogenesis of NAFLD is a multifactorial and multi-step process. Nowadays, a growing body of research suggests the considerable role of the endocannabinoid system (ECS) as a complex cell-signaling system in NAFLD development. Although increased endocannabinoid tone in the liver highly contributes to NAFLD development, the complex effects and impacts of plant-derived cannabinoids in the aspect of NAFLD pathophysiology are yet not fully understood, and effective medications are still in demand. In our review, we present the latest reports describing the role of ECS in NAFLD, focusing primarily on two types of cannabinoid receptors. Moreover, we sum up the recent literature on the clinical use of natural cannabinoids in NAFLD treatment. This review is useful for understanding the importance of ECS in NAFLD development, and it also provides the basis for more extensive clinical phytocannabinoids testing in patients suffering from NAFLD.

NAFLD as a result of inappropriate diet and obesity, may progress to sever conditions such as: type 2 diabetes mellitus or steatohepatitis, and has recently become a prevalent topic of numerous investigations. Due to its dangerous aftermaths, finding new substances, such as polyphenols and their derivatives, which might reduce liver steatosis is the main target of research into NAFLD treatment. Hence, the aim of the present study was to evaluate the effect(s) of enterolactone (ENL), a metabolite of secoisolariciresinol (SECO), on lipid metabolism together with changes in the expression of fatty acid transporters in fatty liver. The experiments were conducted on HepG2 cells incubated with either ENL and/or palmitic acid during 16 h exposure. The expression of selected fatty acid transport proteins: FATP2, FATP5, CD36, FABPpm, ABCA1, MTP, ACBP and L-FABP, as well as the proteins directly involved in lipogenesis (FAS), oxidation pathway (CPT 1), and lipid metabolism (PPARα, LXR, SREBP1c, pAMPK) was estimated by Western Blot. Intra and extracellular lipid contents were assessed by Gas-Liquid Chromatography. The data was analyzed with two-way analysis of variance (ANOVA), and results were considered to be statistically significant at p ≤ 0.05. ENL stimulated extracellular efflux of free fatty acids (FFA) and triacylglicerols (TAG) to the medium, while, it had no influence on FATP-family mediated intracellular fatty acid uptake. Moreover, ENL decreased the expression of CPT 1, pAMPK, PPARα, increased SREBP1c and had no effect on LXR, and FAS content. The findings of our study demonstrate that ENL had opposite effect on liver steatosis in comparison with other polyphenols what suggests that it may be an inactive metabolite. ENL did not affect significantly the intracellular accumulation of FFA, DAG and TAG, yet it promoted their extracellular efflux. Furthermore, it inhibited ß-oxydation and intracellular lipid metabolism what may contribute to the progression of NAFLD.

Obesity-related insulin resistance (IR) and attenuated brain insulin signaling are significant risk factors for neurodegenerative disorders, e.g., Alzheimer's disease. IR and type 2 diabetes correlate with an increased concentration of sphingolipids, a class of lipids that play an essential structural role in cellular membranes and cell signaling pathways. Cannabidiol (CBD) is a nonpsychoactive constituent of Cannabis sativa plant that interacts with the endocannabinoidome. Despite known positive effects of CBD on improvement in diabetes and its aftermath, e.g., anti-inflammatory and anti-oxidant effects, there are no studies evaluating the effect of phytocannabinoids on the brain insulin resistance and sphingolipid metabolism. Our experiment was carried out on Wistar rats that received a high-fat diet and/or intraperitoneal CBD injections. In our study, we indicated inhibition of de novo synthesis and salvage pathways, which resulted in significant changes in the concentration of sphingolipids, e.g., ceramide and sphingomyelin. Furthermore, we observed reduced brain IR and decreased tau protein phosphorylation what might be protective against neuropathologies development. We believe that our research will concern a new possible therapeutic approach with Cannabis -plant derived compounds and within a few years, cannabinoids would be considered as prominent substances for targeting both metabolic and neurodegenerative pathologies.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. The disturbances in the fatty acid composition of stored lipids are more important than the lipid species itself, which may influence the overall effect caused by these molecules. Thus, uncovering time-dependent changes in the fatty acid composition of accumulated lipid fractions after a high fat diet seems to be a new marker of NAFLD occurrence. The experiments were conducted on high fat fed Wistar rats. The blood and liver samples were collected at the end of each experimental week and used to assess the content of lipid fractions and their fatty acid composition by gas liquid chromatography. The expression of proteins from lipid metabolism pathways and of fatty acid exporting proteins were detected by Western blotting. In the same high fat feeding period, decreased de novo lipogenesis, increased β-oxidation and lipid efflux were demonstrated. The observed effects may be the first liver protective mechanisms against lipotoxicity. Nevertheless, such effects were still not sufficient to prevent the liver from proinflammatory lipid accumulation. Moreover, the changes in liver metabolic pathways caused the plasma nervonic acid concentration in sphingomyelin to decrease simultaneously with NAFLD development, which may be a steatosis occurrence prognostic marker.

Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable. Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS. Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies. We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.