title: Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons.
abstract: Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation. We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus vectors to express Gq-coupled modified GPCR, hM3Dq or diphtheria toxin fragment A in orexin neurons. By intraperitoneal injection of clozapine-N oxide in orexin-Cre mice expressing hM3Dq in orexin neurons, we could selectively manipulate the activity of orexin neurons. Pharmacogenetic stimulation of orexin neurons simultaneously increased locomotive activity, food intake, water intake and the respiratory exchange ratio (RER). Elevation of blood glucose levels and RER persisted even after locomotion and feeding behaviors returned to basal levels. Accordantly, 83% ablation of orexin neurons resulted in decreased food and water intake, while 70% ablation had almost no effect on these parameters. Our results indicate that orexin neurons play an integral role in regulation of both feeding behavior and metabolism. This regulation is so robust that greater than 80% of orexin neurons were ablated before significant changes in feeding behavior emerged.
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Inutsuka
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Inui
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Tabuchi
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tsunematsu
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. Electronic address: yamank@riem.nagoya-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D001786:Blood Glucose; D000229:Dependovirus / Q000235:genetics; D004326:Drinking / Q000502:physiology*; D060766:Drinking Water / Q000008:administration & dosage; D004435:Eating / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005822:Genetic Vectors; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins
chemical_list: D001786:Blood Glucose; D060766:Drinking Water; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins
keywords: Feeding; Hypothalamus; Metabolism; Orexin; Pharmacogenetics