title: Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice.
abstract: Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan htsuneki@pha.u-toyama.ac.jp tsasaoka@pha.u-toyama.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Tokai
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Asaoka
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Kanta
authors.initials: K
authors.lastname: Kon
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Anzawa
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.affiliation: Division of Molecular Genetics Research, University of Toyama, Toyama, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takasaki
authors.affiliation: Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama, Japan htsuneki@pha.u-toyama.ac.jp tsasaoka@pha.u-toyama.ac.jp.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001786:Blood Glucose; D002940:Circadian Rhythm; D004837:Epinephrine / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D007031:Hypothalamus / Q000378:metabolism*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism; D000068797:Orexins; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D064446:Orexin Receptors; D000068797:Orexins; D054411:Receptors, Leptin; D004837:Epinephrine