Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity

Am J Physiol Regul Integr Comp Physiol. 2015 Mar 1;308(5):R360-9. doi: 10.1152/ajpregu.00344.2014. Epub 2014 Dec 24.

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.

Keywords: food intake; leptin; nodose ganglion; obesity; oxytocin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Anti-Obesity Agents / administration & dosage*
  • Appetite Depressants / administration & dosage
  • Calcium / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Eating / drug effects*
  • Feeding Behavior / drug effects*
  • Hyperphagia / drug therapy*
  • Hyperphagia / physiopathology
  • Injections, Intraperitoneal
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Obesity / drug therapy*
  • Obesity / physiopathology
  • Oxytocin / administration & dosage*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Sensory System Agents / pharmacology
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / metabolism
  • Solitary Nucleus / physiopathology
  • Time Factors
  • Vagotomy
  • Vagus Nerve / drug effects*
  • Vagus Nerve / metabolism
  • Vagus Nerve / physiopathology
  • Weight Gain / drug effects

Substances

  • Anti-Obesity Agents
  • Appetite Depressants
  • Proto-Oncogene Proteins c-fos
  • Sensory System Agents
  • Oxytocin
  • Calcium