Poster Presentation Australian & New Zealand Obesity Society 2016 Annual Scientific Meeting

NADPH oxidase modulates leptin effects on gastric vagal afferent mechanosensitivity. (#248)

Hui Li 1 2 , Claudine Frisby 1 2 , Gary Wittert 1 2 , Amanda Page 1 2
  1. University of Adelaide, Adelaide, SA, Australia
  2. Nutrition and Metabolism, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA

Leptin, produced locally in the stomach modulates peripheral gastric vagal afferent  satiety signals by a paracrine mechanism of action. In lean, standard laboratory diet (SLD) fed mice, leptin potentiates gastric vagal afferent mucosal receptor responses to mucosal stroking. In contrast in mice with high fat diet (HFD)-induced obesity leptin has no effect on mucosal receptors and inhibits the response of tension receptors to stretch, an effect not observed in lean mice (J Physiol 2013;591:1921-34). The mechanism for this switch in effect of leptin in gastric vagal afferents is unknown. Within the hypothalamus there is evidence to suggest that reactive oxygen species (ROS) production mediates the effect of leptin (Nat Med 2011;17:1121-7). Therefore we determined whether: 1) NOX mRNA and protein are expressed in vagal afferent neurones; and 2) we can mimic leptin effects in HFD conditions by inhibiting NADPH oxidase (NOX), the enzyme responsible for the synthesis of ROS.

The relative expression of NOX isoforms in vagal afferent neurons was NOX2>>NOX4>DUOX2>DUOX1>NOX1>NOX3. In addition, traced gastric vagal afferent neurones were NOX2 positive. Single fibre recordings of gastric vagal afferent tension and mucosal receptors were obtained from lean mice fed ad libitum. Leptin (1nM) potentiated gastric vagal afferent mucosal receptor responses to mucosal stroking; an effect blocked by the NOX inhibitor apocynin (1mM). Leptin had no effect on gastric vagal afferent tension receptors. However, in the presence of apocynin leptin reduced tension receptor responses to stretch.

In conclusion, NOX inhibition mimics the effect of leptin on gastric vagal afferent in HFD-induced obesity. Thus the switch in effect of leptin is likely due to disruption of leptin-NOX signalling pathways.