title: Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity.
abstract: Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Suyama
authors.affiliation: First Department of Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Arai
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Katsurada
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan;
authors.forename: Parmila
authors.initials: P
authors.lastname: Kumari
authors.affiliation: Health Science Service Center, Kanazawa University, Ishikawa, Japan; and.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakabayashi
authors.affiliation: First Department of Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama, Japan;
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan; Division of Adaptation Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Aichi, Japan tyada@jichi.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000200:Action Potentials; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001067:Appetite Depressants / Q000008:administration & dosage; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004435:Eating / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects*; D006963:Hyperphagia / Q000188:drug therapy* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D010121:Oxytocin / Q000008:administration & dosage*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015430:Weight Gain / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D016760:Proto-Oncogene Proteins c-fos; D018689:Sensory System Agents; D010121:Oxytocin; D002118:Calcium
keywords: food intake; leptin; nodose ganglion; obesity; oxytocin