Cannabinoids, eating behaviour, and energy homeostasis

Soon after the discovery of cannabis by western societies, its psychotropic effects overshadowed its medical benefits. How-ever, investigation into the molecular action of the main constituents of cannabis has led to the discovery of an intercellularsignalling system, called the endocannabinoid system (ECS). The ECS comprises a set of molecular components, including en-zymes, signalling lipids and G-protein coupled receptors, which has an outstanding role in modulating eating behaviour andenergy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system,modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk be-tween these brain structures and peripheral organs. Indeed, the ECS is present and functional in metabolically relevant periph-eral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highlysuggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities. In fact, a cannabinoid-based first generation of drugs was developed and marketed. Their failure, due to central side-effects, is leading to a secondgeneration of these drugs unable to cross the blood–brain barrier, as well as other ECS-focused strategies that are still in thepipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be suc-cessfully targeted without significantly affecting other vital processes related to mood and sense of well-being

The role of the endocannabinoid system in eating disorders: pharmacological implications

The endocannabinoid (eCB) system is a widespread intercellular signalling mechanism that plays a critical role in body homoeostasis. It is located in key points involved in food intake and energy expenditure, coordinating all the players involved in energy balance. As such, it has come to be seen as an interesting target for the management of diseases characterized by an imbalanced energy homoeostasis, such as obesity and eating disorders. The aetiology of eating disorders and the molecular systems involved are still largely a mystery. Research has focused on brain circuits where the eCB system plays an important role, such as those related to feeding behaviour and the rewarding properties of food. Accordingly, recent findings have suggested a deregulation of the eCB system in eating disorders. At present, cannabinoid agonists are safe and effective tools in the management of diseases in which weight gain is needed, for example cachexia in AIDS patients. However, studies on the potential therapeutic validity of cannabinoids in eating disorders are scarce and inconclusive. Taken together, all these considerations warrant more preclinical and clinical investigations in the role of the eCB system in eating disorders. Eventually, they may provide novel pharmacological approaches for the treatment of these diseases

Use of Facebook, perceived stress and alcohol consumption among university students

Abstract Analysis of the effect between the use of Facebook, perceived stress and alcohol consumption among young people. A descriptive, correlative and cross-sectional study was carried out. The sample of 1110 young university students from Nuevo León, Mexico, was selected by probability sample. Personal Data and Prevalence of Alcohol Consumption Inventory, Alcohol Use Disorders Identification Test (AUDIT), Facebook Use Identification Test, Perceived Stress Scale were used. The Research Ethics Committee approved it. We observed 6.4% of young people have mentioned that the use of Facebook affected the alcohol consumption. Seeing adds with alcohol on Facebook was related to alcohol consumption (rs = 0,204, p < 0,05). At the time Facebook was used, it was related to the perceived stress (rs = 0,189, p < 0,05). Finally, it was observed that there is a significant impact between the hours and days of use of Facebook, the stress perceived by young people, the age and gender regarding the harmful alcohol consumption among university students (R2 = 30,9%, p = 0,003). Therefore, it is crucial and necessary to consider social networks an important variable to be included in future interventions regarding mental health. Key words Social network, Stress, Consume alcohol, Youn

RPL13A and EEF1A1 Are Suitable Reference Genes for qPCR during Adipocyte Differentiation of Vascular Stromal Cells from Patients with Different BMI and HOMA-IR

Real-time or quantitative PCR (qPCR) is a useful technique that requires reliable reference genes for data normalization in gene expression analysis. Adipogenesis is among the biological processes suitable for this technique. The selection of adequate reference genes is essential for qPCR gene expression analysis of human Vascular Stromal Cells (hVSCs) during their differentiation into adipocytes. To the best of our knowledge, there are no studies validating reference genes for the analyses of visceral and subcutaneous adipose tissue hVSCs from subjects with different Body Mass Index (BMI) and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index. The present study was undertaken to analyze this question. We first analyzed the stability of expression of five potential reference genes: CYC, GAPDH, RPL13A, EEF1A1, and 18S ribosomal RNA, during in vitro adipogenic differentiation, in samples from these types of patients. The expression of RPL13A and EEF1A1 was not affected by differentiation, thus being these genes the most stable candidates, while CYC, GAPDH, and 18S were not suitable for this sort of analysis. This work highlights that RPL13A and EEF1A1 are good candidates as reference genes for qPCR analysis of hVSCs differentiation into adipocytes from subjects with different BMI and HOMA-IR.Instituto de Salud Carlos III (PI10/01947, PI13/02628) with Fondos FEDER and the Consejería de Economía e Innovación, Ciencia y Empleo, Junta de Andalucía (CTS-7895) with Fondos FEDER. R. El Bekay is under a contract Miguel Servet type II (CPII13/00041) from the Instituto de Salud Carlos III. F-JB-S is a recipient of a "Miguel Servet II" research contract (CPII13/00042) and also belongs to the regional "Nicolás Monardes" research program of the Consejería de Salud (C-0070-2012; Junta de Andalucía, Spain). This work was supported by the FIS-Thematic Networks and Co-Operative Research Centres RIRAAF (RD07-0064). JM is under the Programa de Intensificación de la Actividad Investigadora del Sistema Nacional de Salud. AV-R is under a contract Proyectos de I+D+i para jóvenes investigadores from the Ministerio de Economía y Competitividad (SAF2014-60649-JIN). S-YR-Z is recipient of a post-doctoral contract from Consejería de Salud de la Junta de Andalucía (RH-0070-2013)

Early maternal deprivation induces gender-dependent changes on the expression of hippocampal CB(1) and CB(2) cannabinoid receptors of neonatal rats.

Política de acceso abierto tomada de: https://v2.sherpa.ac.uk/id/publication/13858Early maternal deprivation (MD) in rats (24 h, postnatal day 9–10) is a model for neurodevelopmental stress. There are some data proving that MD affects the endocannabinoid system (ECS) in a gender-dependent manner, and that these changes may account for the proposed schizophrenia-like phenotype of MD rats. The impact of MD on cannabinoid receptor distribution in the hippocampus is unknown. The aim of this study is to evaluate the expression of CB1 and CB2 receptors in diverse relevant subregions (DG, CA1, and CA3) of the hippocampus in 13-day-old rats by immunohistochemistry and densitometry. MD induced a significant decrease in CB1 immunoreactivity (more marked in males than in females), which was mainly associated with fibers in the strata pyramidale and radiatum of CA1 and in the strata oriens, pyramidale, and radiatum of CA3. In contrast, MD males and females showed a significant increase in CB2 immunoreactivity in the three hippocampal areas analyzed that was detected in neuropil and puncta in the stratum oriens of CA1 and CA3, and in the polymorphic cell layer of the dentate gyrus. A marked sex dimorphism was observed in CA3, with females exhibiting higher CB1 immunoreactivity than males, and in dentate gyrus, with females exhibiting lower CB2 immunoreactivity than males. These results point to a clear association between developmental stress and dysregulation of the ECS. The present MD procedure may provide an interesting experimental model to further address the role of the ECS in neurodevelopmental mental illnesses such as schizophrenia. © 2008 Wiley-Liss, Inc.Consejería de Salud. Grant Number: PI-0220 Consejería de Innovación, Ciencia y Empresa. Grant Number: P05-CV1-1038 (Junta de Andalucía) Ministerio de Sanidad y Consumo. Grant Numbers: 2006/142, FIS 07/1226 Ministerio de Educación y Ciencia. Grant Number: SAF2006-07523 Red de trastornos adictivos. Grant Number: RD06/0001 Plan Nacional sobre Droga

Overexpression of Cannabinoid CB2 Receptor in the Brain Induces Hyperglycaemia and a Lean Phenotype in Adult Mice

t is well known that the endocannabinoid system, through cannabinoid CB1 receptor activation,has an important role in the main aspects of energy balance (i.e. food intake, energy expenditureand glucose and fat metabolism), orchestrating all the machinery involved in body weight con-trol and energy homeostasis. A number of studies have revealed a crucial role of brain CB1receptors in these processes. However, functional cannabinoid CB2 receptors have also beendescribed in the brain, with no studies addressing their putative role in body weight control andglucose homeostasis. We have tested this hypothesis by analysing fasting-induced feeding, bodyweight, some hypothalamic neuropeptides, glucose tolerance and plasma hormones in an animalmodel specifically overexpressing CB2 receptors in the central nervous system. We found thatspecific overexpression of CB2 receptors in the brain promoted higher basal glucose levels,decreased fasting-induced feeding and, eventually, led to a lean phenotype and glucose intoler-ance. These findings could not be attributed to decreased locomotor activity, increased anxietyor depressive-like behaviours. The expression of relevant neuropeptides such as pro-opiomelano-cortin and galanin in the arcuate nucleus of the hypothalamus was altered but not those of theCB1 receptor. Indeed, no changes in CB1 expression were found in the liver, skeletal muscle andadipose tissue. However, cannabinoid CB1 and CB2 receptor expression in the endocrine pan-creas and glucagon plasma levels were decreased. No changes in plasma adiponectin, leptin,insulin and somatostatin were found. Taken together, these results suggest a role for centralcannabinoid CB2 receptors in body weight control and glucose homeostasis

Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies

The contribution of the endocannabinoid system to dopamine-mediated disorganized behavior in schizophrenia is discussed. We used a model of concurrent stimulation of dopamine D1 and D2 receptors to evaluate the role of this system in dopamine-mediated stereotypies measured in a hole-board test. Pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1 mg/kg) potentiated stereotyped behavior induced by coadministration of the dopamine D1 receptor agonist SKF 38393 (0.05, 0.1 and 1 mg/kg) and the dopamine D2 receptor agonist quinpirole (0.25 mg/kg). Thus, the endocannabinoid system acts as a brake for abnormal behavior associated with dopaminergic overactivation. © 2007 Elsevier B.V. All rights reserved.Peer Reviewe

Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage

The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1–1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4+ T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8+ T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D

NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist—ONO-8130—negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 to B.R.G., PI-0085-2013 to P.I.L., PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Ciencia e Innovación co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G and PI17/01004 to F.J.B.S.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation Ltd (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.M.V. is recipient of a Fellowship from the Ministerio de Ciencia e Innovación co-funded by Fondos FEDER (PRE2018-084907). F.J.B.S. is a recipient of a "Nicolás Monardes" research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. V.C. is supported by a AECC investigator award. CIBERDEM is an initiative of the Instituto de Salud Carlos III

Rich oleocanthal and oleacein extra virgin olive oil and inflammatory and antioxidant status in people with obesity and prediabetes. The APRIL study: A randomised, controlled crossover study

Background: Oleocanthal and oleacein are olive oil phenolic compounds with well known anti inflammatory and anti-oxidant properties. The main evidence, however, is provided by experimental studies. Few human studies have examined the health benefits of olive oils rich in these biophenols. Our aim was to assess the health properties of rich oleocanthal and oleacein extra virgin olive oil (EVOO), compared to those of common olive oil (OO), in people with prediabetes and obesity. Methods: Randomised, double-blind, crossover trial done in people aged 40e65 years with obesity (BMI 30e40 kg/m2 ) and prediabetes (HbA1c 5.7e6.4%). The intervention consisted in substituting for 1 month the oil used for food, both raw and cooked, by EVOO or OO. No changes in diet or physical activity were recommended. The primary outcome was the inflammatory status. Secondary outcomes were the oxidative status, body weight, glucose handling and lipid profile. An ANCOVA model adjusted for age, sex and treatment administration sequence was used for the statistical analysis. Results: A total of 91 patients were enrolled (33 men and 58 women) and finished the trial. A decrease in interferon-g was observed after EVOO treatment, reaching inter-treatment differences (P ¼ 0.041). Total antioxidant status increased and lipid and organic peroxides decreased after EVOO treatment, the changes reaching significance compared to OO treatment (P < 0.05). Decreases in weight, BMI and blood glucose (p < 0.05) were found after treatment with EVOO and not with OO. Conclusions: Treatment with EVOO rich in oleocanthal and oleacein differentially improved oxidative and inflammatory status in people with obesity and prediabetes.Funding for open access charge: Universidad de Málaga/CBU