title: Negative Regulation of Leptin-induced Reactive Oxygen Species (ROS) Formation by Cannabinoid CB1 Receptor Activation in Hypothalamic Neurons.
abstract: The adipocyte-derived, anorectic hormone leptin was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of reactive oxygen species (ROS) levels in arcuate nucleus (ARC) neurons. Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity. Here we investigated the possibility of a negative regulation by CB1 receptors of leptin-mediated ROS formation in the ARC. Through pharmacological and molecular biology experiments we report data showing that leptin-induced ROS accumulation is 1) blunted by arachidonyl-2'-chloroethylamide (ACEA) in a CB1-dependent manner in both the mouse hypothalamic cell line mHypoE-N41 and ARC neuron primary cultures, 2) likewise blocked by a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, troglitazone, in a manner inhibited by T0070907, a PPAR-γ antagonist that also inhibited the ACEA effect on leptin, 3) blunted under conditions of increased endocannabinoid tone due to either pharmacological or genetic inhibition of endocannabinoid degradation in mHypoE-N41 and primary ARC neuronal cultures from MAGL(-/-) mice, respectively, and 4) associated with reduction of both PPAR-γ and catalase activity, which are reversed by both ACEA and troglitazone. We conclude that CB1 activation reverses leptin-induced ROS formation and hence possibly some of the ROS-mediated effects of the hormone by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity. This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels.
authors: From the Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino 61029, Italy and Endocannabinoid Research Group.
authors: Letizia
authors: L
authors: Palomba
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Cristoforo
authors: C
authors: Silvestri
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Roberta
authors: R
authors: Imperatore
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Giovanna
authors: G
authors: Morello
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Fabiana
authors: F
authors: Piscitelli
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Andrea
authors: A
authors: Martella
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy.
authors: Luigia
authors: L
authors: Cristino
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli 80078, Italy vdimarzo@icb.cnr.it.
authors: Vincenzo
authors: V
authors: Di Marzo
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry; D001835:Body Weight; D002186:Cannabinoids / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000737:chemistry; D063388:Endocannabinoids / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006868:Hydrolysis; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D045162:Thiazolidinediones / Q000737:chemistry; D000077288:Troglitazone
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D002186:Cannabinoids; D002839:Chromans; D063388:Endocannabinoids; D020738:Leptin; D047493:PPAR alpha; D047495:PPAR gamma; D011725:Pyridines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; C458508:T 0070907; D045162:Thiazolidinediones; C119325:arachidonyl-2-chloroethylamide; D002374:Catalase; D000077288:Troglitazone
keywords: Cannabinoid; Cannabinoid Receptor Type 1 (CB1); Hypothalamus; Leptin; Reactive Oxygen Species (ROS)