Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

Giovanna Morello, Roberta Imperatore, Letizia Palomba, Carmine Finelli, Giuseppe Labruna, Fabrizio Pasanisi, Lucia Sacchetti, Lorena Buono, Fabiana Piscitelli, Pierangelo Orlando, Vincenzo Di Marzo, Luigia Cristino

Research output: Contribution to journalArticle

Abstract

In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocytestimulating 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 δ9-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 extracellularsignal- regulated kinase 1/2 activation- and STAT3 inhibitionmediated 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 ofmice. 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 ã-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.

Original languageEnglish
Pages (from-to)4759-4764
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number17
DOIs
Publication statusPublished - Apr 26 2016

Keywords

  • 2-arachidonoylglycerol
  • Cannabinoid type 1 receptor
  • Hypocretin-1
  • Hypothalamus
  • α-melanocyte-stimulating hormone

ASJC Scopus subject areas

  • General

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  • Cite this

    Morello, G., Imperatore, R., Palomba, L., Finelli, C., Labruna, G., Pasanisi, F., Sacchetti, L., Buono, L., Piscitelli, F., Orlando, P., Di Marzo, V., & Cristino, L. (2016). Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling. Proceedings of the National Academy of Sciences of the United States of America, 113(17), 4759-4764. https://doi.org/10.1073/pnas.1521304113