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Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness
Ken Soderstrom, Justin L Poklis, Aron H Lichtman
BMC Neuroscience , 2011, DOI: 10.1186/1471-2202-12-3
Abstract: We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG) and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system.Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.Zebra finches learn a song during distinct periods of vocal development [1]. Exposure to cannabinoid agonists during these periods alters vocal development by reducing both song stereotypy and the number of notes incorporated into mature song produced in adulthood [2,3]. This, combined with evidence for distinct developmental regulation of CB1 cannabinoid receptor expression during periods of song learning [4], suggests a role for endogenous cannabinoid signaling in normal vocal developmental processes. Vocal learning and production in zebra finches is associated with marked physiological changes within distinct regions of telencephalon (e.g. lMAN, Area X, auditory Field L2, RA) and thalamus (DLM, ovoidalis) known to be critical for song perception, production and learning. Each of these regions distinctly and densely expresses CB1 receptors [3]. Normal development in song regions is associated with gross anatomical changes in region volume, neuron number and density, both increases and decreases in axonal interconnections between song regions, and changes in synaptic densities. Cannabinoid-altered vocal development implies that exogenous agonist exposure must somehow alter some or all of these processes responsible for critical periods of song learning. We are currently working to identify which processes are modified by developmental cannabinoid exposure and the mechanism(s) responsible.Distinct song region CB1 receptor expression imp
The Endocannabinoid, Anandamide, Induces Cannabinoid Receptor-Independent Cell Death in Renal Proximal Tubule Cells  [PDF]
Monika Schlosser, Heike L?ser, S?ren V. Siegmund, Manuel Montesinos-Rongen, Laura Bindila, Beat Lutz, David A. Barrett, Sarir Sarmad, Catharine A. Ortori, Veronika Grau, Melanie von Brandenstein, Jochen W.U. Fries
CellBio (CellBio) , 2017, DOI: 10.4236/cellbio.2017.64004
Abstract: Background: The endocannabinoid (EC) system is well characterized in the central nervous system but scarcely studied in peripheral organs. In this paper, we newly identify the effect of the EC anandamide (AEA) upon renal proximal tubule cells. Methods: Measurement of lactate dehydrogenase (LDH) release after treatment of primary renal proximal tubule cells (RPTEC) and renal carcinoma cell line (Caki-1) with AEA, arachidonic acid (AA), ethanolamide (EtAm), EC receptor CB1 antagonist (AM251), CB2 receptor antagonist (SR144528), TRPV1 receptor antagonist (capsazepine), degradation enzyme fatty acid amide hydrolase (FAAH) antagonist (URB597), antioxidants GSH-EE; Trolox, GSH depletor BSO, membrane cholesterol depletor (MCD), apoptosis inhibitor zVAD, necroptosis inhibitor Nec-1 or ferroptosis inhibitor Fer-1. Western blot and qRT-PCR analysis plus determination of reactive oxygen species (ROS) via H2-DCFDA were performed. Histology for EC enzymes, N-acetylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and FAAH, as well as the determination of physiological levels of ECs in human and rat renal tissue via liquid chromatography were conducted. Results: AEA both dose- and time-dependently induces cell death in RPTEC and Caki-1 within hours, characterized by cell blebbing, not influenced by blocking the described EC receptors by AM251, SR144528, capsazepine or FAAH by URB597 or MCD. Cell death is mediated via ROS. There is no difference found in the histology of the enzymes FAAH and NAPE-PLD in human renal tissue with interstitial nephritis. Blocking of apoptotic, necroptotic or ferroptotic cell death does not lead to a reduction in LDH release in vitro. Conclusion: The endocannabinoid anandamide induces cell death in renal proximal tubule cell in a time- and dose-dependent manner. This pathway is mediated via ROS and is independent of cannabinoid receptors, membrane cholesterol or FAAH activity.
Frequency-Dependent Cannabinoid Receptor-Independent Modulation of Glycine Receptors by Endocannabinoid 2-AG  [PDF]
Natalia Lozovaya,Marat Mukhtarov,Piotr Bregestovski
Frontiers in Molecular Neuroscience , 2011, DOI: 10.3389/fnmol.2011.00013
Abstract: Endocannabinoids are known as retrograde messengers, being released from the postsynaptic neuron and acting on specific presynaptic G-protein-coupled cannabinoid (CB) receptors to decrease neurotransmitter release. Also, at physiologically relevant concentrations cannabinoids can directly modulate the function of voltage-gated and receptor-operated ion channels. Using patch-clamp recording we analyzed the consequences of the direct action of an endocannabinoid, 2-arachidonoylglycerol (2-AG), on the functional properties of glycine receptor channels (GlyRs) and ionic currents in glycinergic synapses. At physiologically relevant concentrations (0.1–1 μM), 2-AG directly affected the functions of recombinant homomeric α1H GlyR: it inhibited peak amplitude and dramatically enhanced desensitization. The action of 2-AG on GlyR-mediated currents developed rapidly, within ~300 ms. Addition of 1 μM 2-AG strongly facilitated the depression of glycine-induced currents during repetitive (4–10 Hz) application of short (2 ms duration) pulses of glycine to outside-out patches. In brainstem slices from CB1 receptor knockout mice, 2-AG significantly decreased the extent of facilitation of synaptic currents in hypoglossal motoneurons during repetitive (10–20 Hz) stimulation. These observations suggest that endocannabinoids can modulate postsynaptic metaplasticity of glycinergic synaptic currents in a CB1 receptor-independent manner.
Absence of Perilipin 2 Prevents Hepatic Steatosis, Glucose Intolerance and Ceramide Accumulation in Alcohol-Fed Mice  [PDF]
Rotonya M. Carr, Giselle Peralta, Xiaoyan Yin, Rexford S. Ahima
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097118
Abstract: Background Perilipin 2 (Plin2) is a lipid droplet protein that has roles in both lipid and glucose homeostasis. An increase in Plin2 in liver is associated with the development of steatosis, glucose intolerance, and ceramide accumulation in alcoholic liver disease. We investigated the role of Plin2 on energy balance and glucose and lipid homeostasis in wildtype and Plin2 knockout (Plin2KO) mice chronically fed a Lieber-DeCarli liquid ethanol or control diet for six weeks. Methods We performed in vivo measurements of energy intake and expenditure; body composition; and glucose tolerance. After sacrifice, liver was dissected for histology and lipid analysis. Results We found that neither genotype nor diet had a significant effect on final weight, body composition, or energy intake between WT and Plin2KO mice fed alcohol or control diets. Additionally, alcohol feeding did not affect oxygen consumption or carbon dioxide production in Plin2KO mice. We performed glucose tolerance testing and observed that alcohol feeding failed to impair glucose tolerance in Plin2KO mice. Most notably, absence of Plin2 prevented hepatic steatosis and ceramide accumulation in alcohol-fed mice. These changes were related to downregulation of genes involved in lipogenesis and triglyceride synthesis. Conclusions Plin2KO mice chronically fed alcohol are protected from hepatic steatosis, glucose intolerance, and hepatic ceramide accumulation, suggesting a critical pathogenic role of Plin2 in experimental alcoholic liver disease.
Hepatic Glucose Intolerance Precedes Hepatic Steatosis in the Male Aromatase Knockout (ArKO) Mouse  [PDF]
Michelle L. Van Sinderen, Gregory R. Steinberg, Sebastian B. J?rgensen, Sarah Q. To, Kevin C. Knower, Colin D. Clyne, Jane Honeyman, Jenny D. Chow, Kerrie A. Herridge, Margaret E. E. Jones, Evan R. Simpson, Wah Chin Boon
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087230
Abstract: Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle. Estrogen-deficient male ArKO mice showed increased gonadal adiposity which was significantly reduced upon 17β-estradiol (E2) treatment. Concurrently, elevated ArKO serum leptin levels were significantly reduced upon E2 treatment and lowered serum adiponectin levels were restored to wild type levels. Three-month-old male ArKO mice were hyperglycemic, and both glucose and pyruvate intolerant. These phenotypes continued through to 6 months of age, highlighting a loss of glycemic control. ArKO livers displayed changes in gluconeogenic enzyme expression, and in insulin signaling pathways upon E2 treatment. Liver triglycerides were increased in the ArKO males only after 6 months of age, which could be reversed by E2 treatment. No differences were observed in insulin-stimulated ex vivo muscle glucose uptake nor changes in ArKO adipose tissue and muscle insulin signaling pathways. Therefore, we conclude that male ArKO mice develop hepatic glucose intolerance by the age of 3 months which precedes the sex-specific development of hepatic steatosis. This can be reversed upon the administration of exogenous E2.
Hepatic Rather Than Cardiac Steatosis Relates to Glucose Intolerance in Women with Prior Gestational Diabetes  [PDF]
Yvonne Winhofer, Martin Kr??ák, Peter Wolf, Andrea Tura, Christian-Heinz Anderwald, Lana Kosi, Gert Reiter, Giovanni Pacini, Siegfried Trattnig, Anton Luger, Michael Krebs, Alexandra Kautzky-Willer
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091607
Abstract: Background Increased myocardial lipid accumulation has been described in patients with pre- and overt type 2 diabetes and could underlie the development of left-ventricular dysfunction in metabolic diseases (diabetic cardiomyopathy). Since women with prior gestational diabetes (pGDM) display a generally young population at high risk of developing diabetes and associated cardiovascular complications, we aimed to assess whether myocardial lipid accumulation can be detected at early stages of glucose intolerance and relates to markers of hepatic steatosis (Fatty Liver Index), cardiac function, insulin sensitivity and secretion. Methods Myocardial lipid content (MYCL), left-ventricular function (1H-magnetic-resonance-spectroscopy and -imaging), insulin sensitivity/secretion (oral glucose tolerance test) and the fatty liver index (FLI) were assessed in 35 pGDM (45.6±7.0 years, 28.3±4.8 kg/m2) and 14 healthy control females (CON; 44.7±9.8 years, 26.1±2.5 kg/m2), matching for age and body-mass-index (each p>0.1). Results Of 35 pGDM, 9 displayed normal glucose tolerance (NGT), 6 impaired glucose regulation (IGR) and 20 had been already diagnosed with type 2 diabetes (T2DM). MYCL and cardiac function were comparable between pGDM and CON; in addition, no evidence of left-ventricular dysfunction was observed. MYCL was inversely correlated with the ejection fraction in T2DM (R = ?0.45, p<0.05), while the FLI was tightly correlated with metabolic parameters (such as HbA1C, fasting plasma glucose and HDL-cholesterol) and rose along GT-groups. Conclusions There is no evidence of cardiac steatosis in middle-aged women with prior gestational diabetes, suggesting that cardiac complications might develop later in the time-course of diabetes and may be accelerated by the co-existence of further risk factors, whereas hepatic steatosis remains a valid biomarker for metabolic diseases even in this rather young female cohort.
Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis  [PDF]
Vanessa Deveaux, Thomas Cadoudal, Yasukatsu Ichigotani, Fatima Teixeira-Clerc, Alexandre Louvet, Sylvie Manin, Jeanne Tran-Van Nhieu, Marie Pierre Belot, Andreas Zimmer, Patrick Even, Patrice D. Cani, Claude Knauf, Remy Burcelin, Adeline Bertola, Yannick Le Marchand-Brustel, Philippe Gual, Ariane Mallat, Sophie Lotersztajn
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005844
Abstract: Background Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. Methodology Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 ?/?). Principal Findings In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 ?/? mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 ?/? mice. Conclusion/Significance These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorders.
Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study  [PDF]
Jakub Fichna, JodiAnne T. Wood, Malvina Papanastasiou, Subramanian K. Vadivel, Piotr Oprocha, Maciej Sa?aga, Marta Sobczak, Anna Mokrowiecka, Adam I. Cygankiewicz, Piotr K. Zakrzewski, Ewa Ma?ecka-Panas, Wanda M. Krajewska, Piotr Ko?cielniak, Alexandros Makriyannis, Martin A. Storr
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0085073
Abstract: Aims Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. Methods AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Results Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. Conclusion IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.
Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior  [PDF]
Claudio Zanettini,Leigh V. Panlilio,József Haller
Frontiers in Behavioral Neuroscience , 2011, DOI: 10.3389/fnbeh.2011.00057
Abstract: Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.
Chronic Endocannabinoid System Stimulation Induces Muscle Macrophage and Lipid Accumulation in Type 2 Diabetic Mice Independently of Metabolic Endotoxaemia  [PDF]
Lucie Geurts, Giulio G. Muccioli, Nathalie M. Delzenne, Patrice D. Cani
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055963
Abstract: Aims Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. Methods Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT) diet, one-half of each group of mice were challenged with a high fat (HF) diet for the following 3-week period. Results Under basal conditions (control diet), chronic CB receptor agonist treatment (i.e., 6 weeks) induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression) in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression) in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle's lipid content without affecting the body weight or the fat mass. Conclusion Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.
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