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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-04, Vol.113 (17), p.4759-4764
• Main Authors: Morello, Giovanna, Imperatore, Roberta, Palomba, Letizia, Finelli, Carmine, Labruna, Giuseppe, Pasanisi, Fabrizio, Sacchetti, Lucia, Buono, Lorena, Piscitelli, Fabiana, Orlando, Pierangelo, Di Marzo, Vincenzo, Cristino, Luigia
• Format: Article
• Language: English
• Subjects: Adult; alpha-MSH - metabolism; Animals; Anterior Hypothalamic Nucleus - metabolism; Anterior Hypothalamic Nucleus - pathology; Biological Sciences; Biosynthesis; Cells, Cultured; Endocannabinoids - metabolism; Homeostasis; Humans; Male; Mice; Mice, Inbred C57BL; Neural Inhibition; Neurons; Neurons - metabolism; Neuropeptides; Obesity; Obesity - metabolism; Orexins - metabolism; Pro-Opiomelanocortin - metabolism; Proteins; Satiety Response; Signal Transduction; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1521304113

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 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 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.