title: Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons.
abstract: Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.
authors: Endocannabinoid Research Group, Institute of Cybernetics Eduardo Caianiello, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy. l.cristino@cib.na.cnr.it
authors: Luigia
authors: L
authors: Cristino
authors: Giuseppe
authors: G
authors: Busetto
authors: Roberta
authors: R
authors: Imperatore
authors: Ida
authors: I
authors: Ferrandino
authors: Letizia
authors: L
authors: Palomba
authors: Cristoforo
authors: C
authors: Silvestri
authors: Stefania
authors: S
authors: Petrosino
authors: Pierangelo
authors: P
authors: Orlando
authors: Marina
authors: M
authors: Bentivoglio
authors: Kenneth
authors: K
authors: Mackie
authors: Vincenzo
authors: V
authors: Di Marzo
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000068797:Orexins; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: food intake; high-fat diet; orexin-A/hypocretin 1; retrograde signaling
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