title: Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons.
abstract: Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na(+),K(+)-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na(+) concentration in single ARC neurons that subsequently exhibited [Ca(2+)]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca(2+)]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca(2+)]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan; Department of Neurosurgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kurita
authors.affiliation: Department of Surgery, Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Xu
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Putra
authors.initials: P
authors.lastname: Santoso
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Yifei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Arai
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Darambazar
authors.initials: D
authors.lastname: Gantulga
authors.affiliation: Department of Psychiatry, Imamura-bunin Hospital, Kagoshima, Kagoshima, Japan;
authors.forename: Shinji
authors.initials: S
authors.lastname: Muroya
authors.affiliation: Department of Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Alan K
authors.initials: AK
authors.lastname: Lefor
authors.affiliation: First Department of Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan; and.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.affiliation: Department of Neurosurgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan;
authors.forename: Eiju
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan; Department of Developmental Physiology, Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan tyada@jichi.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics*; D005247:Feeding Behavior / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000502:physiology*
chemical_list: D054369:Agouti-Related Protein; D009478:Neuropeptide Y; D000255:Adenosine Triphosphate; C541459:Atp1a3 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose
keywords: ATP; Na+,K+-ATPase; SSA412; agouti-related protein; arcuate nucleus; fasting; feeding behavior; ghrelin; glucose; glucose-inhibited neuron; neuropeptide Y; ouabain; α3-isoform