Gastric vagal afferent modulation by leptin is influenced by food intake status

Journal of Physiology - Tập 591 Số 7 - Trang 1921-1934 - 2013
Stephen J. Kentish1, Tracey A. O’Donnell2, Nicole J. Isaacs1, Richard L. Young1,3,2, Hui Li1, Andrea M. Harrington1,2, Stuart M. Brierley1,3,2, Gary Wittert1, L. Ashley Blackshaw1,4, Amanda J. Page1,3,2
1Discipline of Medicine
2Nerve-Gut Research Laboratory, Room 1-216-H, Level 1, Hanson Institute, Royal Adelaide Hospital
3Discipline of Physiology, University of Adelaide, Adelaide, South Australia
4Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary, University of London, London, UK

Tóm tắt

Key points Obesity occurs when energy intake exceeds expenditure, and the excess energy is stored as fat. We show that, after a 14 h food deprivation or 12 weeks consumption of a high‐fat diet, gastric vagal afferent responses to mechanical stimulation in the presence of the satiety peptide leptin are altered. Leptin has an excitatory effect on gastric mucosal vagal afferents, which is abolished after food restriction or prolonged excess. In contrast, leptin has an inhibitory effect on gastric tension‐sensitive afferents, but only after food restriction or energy excess conditions. These changes in the response to leptin in the stomach, after food restriction or prolonged high‐fat feeding, occur in such a manner as to facilitate an increase in food intake in both conditions. Abstract  Energy intake is strongly influenced by vagal afferent signals from the stomach, and is also modulated by leptin. Leptin may be secreted from gastric epithelial cells, so we aimed to determine the direct effect of leptin on gastric vagal afferents under different feeding conditions. Female C57BL/6 mice were fed standard laboratory diet, high‐fat diet or were food restricted. The expression of leptin receptor (Lep‐R) and its signal transduction molecules in vagal afferents was determined by retrograde tracing and reverse‐transcription polymerase chain reaction, and the relationship between leptin‐immunopositive cells and gastric vagal afferent endings determined by anterograde tracing and leptin immunohistochemistry. An in vitro preparation was used to determine the functional effects of leptin on gastric vagal afferents and the second messenger pathways involved. Leptin potentiated vagal mucosal afferent responses to tactile stimuli, and epithelial cells expressing leptin were found close to vagal mucosal endings. After fasting or diet‐induced obesity, potentiation of mucosal afferents by leptin was lost and Lep‐R expression reduced in the cell bodies of gastric mucosal afferents. These effects in diet‐induced obese mice were accompanied by a reduction in anatomical vagal innervation of the gastric mucosa. In striking contrast, after fasting or diet‐induced obesity, leptin actually inhibited responses to distension in tension receptors. The inhibitory effect on gastric tension receptors was mediated through phosphatidylinositol 3‐kinase‐dependent activation of large‐conductance calcium‐activated potassium channels. The excitatory effect of leptin on gastric mucosal vagal afferents was mediated by phospholipase C‐dependent activation of canonical transient receptor potential channels. These data suggest the effect of leptin on gastric vagal afferent excitability is dynamic and related to the feeding state. Paradoxically, in obesity, leptin may reduce responses to gastric distension following food intake.

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Journal of Physiology

Tập 591 Số 7

1921-1934

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