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Activation of the Sympathetic Nervous System Mediates Hypophagic and Anxiety-Like Effects of CB1 Receptor Blockade

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Activation of the Sympathetic Nervous System Mediates Hypophagic and Anxiety-Like Effects of CB1 Receptor Blockade Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1 receptor blockade Luigi Bellocchioa,1, Edgar Soria-Gómezb,c,1, Carmelo Quartad, Mathilde Metna-Laurentb,c, Pierre Cardinalb,c, Elke Binderb,c, Astrid Cannichb,c, Anna Delamarreb,c, Martin Häringe, Mar Martín-Fontechaf, David Vegaa, Thierry Leste-Lasserreb,c, Dusan Bartschg, Krisztina Monorye, Beat Lutze, Francis Chaouloffb,c, Uberto Pagottod, Manuel Guzmana,2, Daniela Cotab,c,2, and Giovanni Marsicanob,c,2,3 aDepartment of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, School of Biology, Complutense University-Instituto Universitario de Investigación Neuroquímica, 28040 Madrid, Spain; bNeurocentre Magendie, Physiophatologie de la Plasticité Neuronale, Institut National de la Santé et de la Recherche Médicale, U862, F-33000 Bordeaux, France; cNeurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, University of Bordeaux, F-33000 Bordeaux, France; dEndocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater University of Bologna, I-40138 Bologna, Italy; eInstitute of Physiological Chemistry, University Medical Center, D-55128 Mainz, Germany; fDepartment of Organic Chemistry, Complutense University, 28040 Madrid, Spain; and gDepartment of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved February 11, 2013 (received for review October 25, 2012) Complex interactions between periphery and the brain regulate peripheral mechanisms (2, 3). Few studies have suggested that food intake in mammals. Cannabinoid type-1 (CB1) receptor antag- CB1 receptor signaling could regulate food intake at peripheral onists are potent hypophagic agents, but the sites where this acute sites (2, 6, 7). Fasting triggers the synthesis of gastrointestinal action is exerted and the underlying mechanisms are not fully elu- endocannabinoids, and endocannabinoids produced in the gas- cidated. To dissect the mechanisms underlying the hypophagic ef- trointestinal tract may regulate food (mainly fat) intake (6). The peripheral sympathetic nervous system (SNS) is one of the main fect of CB1 receptor blockade, we combined the acute injection of the CB receptor antagonist rimonabant with the use of conditional mechanisms engaged by CB1 receptor-dependent signaling for 1 the modulation of energy balance (8) and genetic or pharma- CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experi- cological CB1 receptor blockade increases plasma levels of nor- ments revealed that CB receptor signaling in many specificbrain epinephrine (8, 9). In turn, SNS activity regulates meal patterns 1 (10) and is oppositely regulated by the organism’s energy status, neurons is dispensable for the acute hypophagic effects of rimona- being decreased by fasting and increased by feeding (11). Finally, bant. CB1 receptor antagonist-induced hypophagia was fully abol- β visceral afferents also play an important role in transmitting nu- ished by peripheral blockade of -adrenergic transmission, trient-derived intestinal signals to the brainstem, where glutamate suggesting that this effect is mediated by increased activity of the and NMDA receptors modulate visceral sensory signaling path- sympathetic nervous system. Consistently, we found that rimona- ways, ultimately regulating food intake (12). Interestingly, the in- bant increases gastrointestinal metabolism via increased peripheral terplay between SNS and brainstem glutamatergic activity also β-adrenergic receptor signaling in peripheral organs, including the regulates other brain functions, such as fear and anxiety responses gastrointestinal tract. Blockade of both visceral afferents and gluta- (13), and alterations in these functions represent the main side- matergic transmission in the nucleus tractus solitarii abolished rimo- effects of rimonabant use in humans (14). nabant-induced hypophagia. Importantly, these mechanisms were In this study, we systematically investigated the potential sites specifically triggered by lipid-deprivation, revealing a nutrient- and the mechanisms of the acute and rapid hypophagic action of specific component acutely regulated by CB1 receptor blockade. rimonabant under fasting/refeeding, as well as its central effects Finally, peripheral blockade of sympathetic neurotransmission also on fear- and anxiety-like behaviors. blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, Results independently of their site of origin, important effects of CB1 re- CB1 Receptors in Different Brain Neuron Types Are Dispensable for ceptor blockade are expressed via activation of peripheral sympa- the Rapid Hypophagic Effect of Rimonabant. The acute hypophagic thetic activity. Thus, CB1 receptors modulate bidirectional circuits effect of rimonabant depends on CB1 receptors expressed in between the periphery and the brain to regulate feeding and neurons (8). Thus, we tried to identify the exact neuronal pop- other behaviors. ulation involved in this phenomenon. Rimonabant bore no effect on fasting-induced food intake in constitutive CB1-KO (5, 15) fear and anxiety | sympathetic system and in conditional mutant mice lacking CB1 receptor expression in forebrain and sympathetic neurons (8, 16) (CaMK-CB1-KO) ppropriate feeding responses are determined by complex Across-talks between the central nervous system and periph- Author contributions: L.B., F.C., M.G., D.C., and G.M. designed research; L.B., E.S.-G., C.Q., eral organs (1). The endocannabinoid system (ECS) is an im- M.M.-L., P.C., E.B., A.C., A.D., M.M.-F., D.V., T.L.-L., U.P., and M.G. performed research; portant modulator of central and peripheral regulation of energy M.H., D.B., K.M., B.L., and G.M. contributed new reagents/analytic tools; L.B., E.S.-G., C.Q., metabolism (2, 3). In the brain, endogenous and exogenous M.M.-L., P.C., M.M.-F., F.C., M.G., D.C., and G.M. analyzed data; and L.B., E.S.-G., U.P., cannabinoids oppositely regulate food intake, according to the M.G., D.C., and G.M. wrote the paper. neuronal population involved (4). On the other hand, the canna- The authors declare no conflict of interest. This article is a PNAS Direct Submission. binoid type-1 (CB1) receptor antagonist rimonabant (SR141716) acutely induces hypophagia (5), but the sites and the mechanisms 1L.B. and E.S.-G. contributed equally to this work. involved are not well defined yet. 2M.G., D.C., and G.M. contributed equally to this work. CB1 receptors control the activity of many neurotransmitter 3To whom correspondence should be addressed. E-mail: [email protected]. systems involved in central regulation of food intake (2). How- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ever, the ECS also regulates food intake and energy balance via 1073/pnas.1218573110/-/DCSupplemental. 4786–4791 | PNAS | March 19, 2013 | vol. 110 | no. 12 www.pnas.org/cgi/doi/10.1073/pnas.1218573110 Downloaded by guest on September 28, 2021 (Fig. S1 A and B). Mice characterized by the deletion of CB1 To test the role of CB1 receptors in VMH neurons, we crossed receptors, either from cortical glutamatergic neurons (Glu-CB1- CB1-floxed mice with SF1-Cre mice, characterized by the ex- KO) or from GABAergic neurons (GABA-CB1-KO), respectively pression of the recombinase under the regulatory sequences of (17, 18), oppositely respond to fasting-induced food intake (4). the steroidogenic factor-1 (SF1), leading to recombination in the Thus, CB receptors expressed on inhibitory or cortical excitatory VMH, pituitary gland, and gonads (21). SF1-CB1-KO mice dis- 1 ∼ E brain neurons might mediate rimonabant hypophagic effect. Ve- played 80% CB1 receptor deletion in the VMH (Fig. S1 ) and E hicle-treated Glu-CB1-KO ate less than their WT littermates (Fig. showed a reduced fasting-induced hyperphagia (Fig. 1 ). How- 1A), whereas GABA-CB1-KO displayed a hyperphagic phenotype ever, the hypophagic effect of rimonabant was still present (Fig. E (Fig. 1B) (4). Surprisingly, however, rimonabant administration 1 ). Thus, VMH CB1 receptors are required for the endogenous similarly reduced food intake in WT, Glu-CB1-KO (Fig. 1A), and control of fasting-induced food intake, but they are dispensable GABA-CB1-KO mice (Fig. 1B), with no significant interaction for the hypophagic effect of rimonabant. between the factors “genotype” and “treatment.” β WT and TPH2-CB1-KO littermates (19), in which the CB1 gene Blockade of Peripheral -Adrenergic Receptors Prevents Rimonabant- is deleted in the raphe nucleus but not in other brain regions (Fig. Induced Hypophagia in Fasting and Lipoprivic Conditions. The SNS 1C and Fig. S1C), consumed a comparable amount of food and plays an important role in the regulation of food intake, partic- β showed a similar acute response to rimonabant under fasting- ularly through the activation of peripheral -adrenergic receptors refeeding conditions (Fig. 1C), suggesting that blockade of CB (22, 23), and CB1 receptors can inhibit central and peripheral 1 norepinephrine (NE) release (24, 25). The systemic injection of receptor signaling on serotonergic neurons is dispensable for β rimonabant-induced
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