title: Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling.
abstract: In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocyte-stimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB1R) on the plasma membrane. OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana's psychotropic and appetite-inducing component Δ(9)-tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB1R. We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB1R-induced and extracellular-signal-regulated kinase 1/2 activation- and STAT3 inhibition-mediated suppression of Pomc gene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/ob and high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice. Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease. These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy; Department of Neurological and Movement Sciences, University of Verona, 37137 Verona, Italy;
authors.forename: Giovanna
authors.initials: G
authors.lastname: Morello
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo," 61029 Urbino, Italy;
authors.forename: Letizia
authors.initials: L
authors.lastname: Palomba
authors.affiliation: Interuniversity Center for Research and Study of Obesity, Department of Clinical and Experimental Medicine, Federico II University Hospital, 80131 Naples, Italy;
authors.forename: Carmine
authors.initials: C
authors.lastname: Finelli
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Diagnostic and Nuclear Research, 80131 Naples, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Labruna
authors.affiliation: Interuniversity Center for Research and Study of Obesity, Department of Clinical and Experimental Medicine, Federico II University Hospital, 80131 Naples, Italy;
authors.forename: Fabrizio
authors.identifier: http://orcid.org/0000-0003-4224-7821
authors.initials: F
authors.lastname: Pasanisi
authors.affiliation: Centro di Ingegneria Genetica-Advanced Biotechnology (Società Cooperativa a Responsabilità Limitata), 80131 Naples, Italy;
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy; Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Cantoblanco, Spain;
authors.forename: Lorena
authors.initials: L
authors.lastname: Buono
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Institute of Protein Biochemistry, National Research Council, 80131 Naples, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy; luigia.cristino@icb.cnr.it.
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
mesh_terms: D000328:Adult; D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012528:Satiety Response; D015398:Signal Transduction; D015854:Up-Regulation; D000521:alpha-MSH / Q000378:metabolism*
chemical_list: D063388:Endocannabinoids; D000068797:Orexins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin
keywords: 2-arachidonoylglycerol; cannabinoid type 1 receptor; hypocretin-1; hypothalamus; α–melanocyte-stimulating hormone