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      Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets

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          Abstract

          Lipid signals derived from lipolysis and membrane phospholipids play an important role in glucose-stimulated insulin secretion (GSIS), though the exact secondary signals remain unclear. Previous reports have documented a stimulatory role of exogenously added mono-acyl-glycerol (MAG) on insulin secretion from cultured β-cells and islets. In this report we have determined effects of increasing intracellular MAG in the β-cell by inhibiting mono-acyl-glycerol lipase (MGL) activity, which catalyzes the final step in triacylglycerol breakdown, namely the hydrolysis of MAG to glycerol and free fatty acid (FA). To determine the role of MGL in GSIS, we used three different pharmacological agents (JZL184, MJN110 and URB602). All three inhibited GSIS and depolarization-induced insulin secretion in INS-1 (832/13). JZL184 significantly inhibited both GSIS and depolarization-induced insulin secretion in rat islets. JZL184 significantly decreased lipolysis and increased both mono- and diacyglycerol species in INS-1 cells. Analysis of the kinetics of GSIS showed that inhibition was greater during the sustained phase of secretion. A similar pattern was observed in the response of Ca 2+ to glucose and depolarization but to a lesser degree suggesting that altered Ca 2+ handling alone could not explain the reduction in insulin secretion. In addition, a significant reduction in long chain-CoA (LC-CoA) was observed in INS-1 cells at both basal and stimulatory glucose following inhibition of MGL. Our data implicate an important role for MGL in insulin secretion.

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          Most cited references 38

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          A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.

          Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that approximately 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.
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            Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects

            2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for anandamide, is mediated by fatty acid amide hydrolase (FAAH) and, for 2-AG, is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, intimating a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL, JZL184, that, upon administration to mice, raises brain 2-AG by 8-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia, and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
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              Metabolic signaling in fuel-induced insulin secretion.

              The pancreatic islet β cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in β cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 February 2016
                2016
                : 11
                : 2
                Affiliations
                Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts, United States of America
                Monash University, AUSTRALIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BEC JTD CAB KAE. Performed the experiments: CAB KAE NEB. Analyzed the data: CAB KAE BEC JTD. Wrote the paper: KAE. Edited the manuscript: KAE CAB NEB BEC JTD.

                Article
                PONE-D-15-47673
                10.1371/journal.pone.0149008
                4750965
                26867016
                © 2016 Berdan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 6, Tables: 0, Pages: 14
                Product
                Funding
                This work was supported by the National Institutes of Health grant number DK74778, National Institutes of Health grant number DK35914. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Insulin Secretion
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Insulin Secretion
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Insulin Secretion
                Physical sciences
                Chemistry
                Polymer chemistry
                Monomers (Chemistry)
                Glycerol
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Lipid Signaling
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Hydrolases
                Lipases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Hydrolases
                Lipases
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Secretion
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Secretion
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Biology and Life Sciences
                Biochemistry
                Lipids
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                All relevant data are within the paper.

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