Diet-induced modulation of vagal sensory signaling
Open Access
- Author:
- Troy, Amanda Erin
- Graduate Program:
- Anatomy
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 29, 2014
- Committee Members:
- Kirsteen Nairn Browning, Dissertation Advisor/Co-Advisor
Gregory Michael Holmes, Committee Member
Andras Hajnal, Committee Member
Patricia Mc Laughlin, Committee Member
Ann Ouyang, Committee Chair/Co-Chair - Keywords:
- vagus
vagal afferent
5-HT
glucose
high fat diet
protein kinase C
electrophysiology
immunocytochemistry
5-HT3 receptor - Abstract:
- As obesity levels continue to rise in developed nations, it becomes increasingly important to determine the mechanisms underlying obesity. Ingested food induces the release of various neurohormones and neuropeptides, such as 5-HT, that activate the sensory vagus, which then relays the signal to the brain. These vagally-mediated satiety signals are capable of a substantial amount plasticity and modulation in response to physiological demands. The present work will investigate the effects of high fat diet (HFD) exposure on the ability of glucose to modulate the 5-HT-induced response of gastric projecting vagal afferent neurons. In response to changing circulating glucose levels, vagal afferent neurons are able to alter their membrane-associated 5-HT3 receptor profile and afferent nerve function centrally at the level of the nucleus of the tractus solitaries and peripherally at the level of the nodose ganglion. In several peripheral and central tissues, protein kinase C (PKC) activity is correlated with glucose level and, in the present study, the glucose-dependent modulation of 5-HT3 receptor density and function appears to be mediated via a PKC and/or PKC pathway. The rapid timescale of electrophysiological effects suggest that glucose may modulate vagal sensory signaling on a minute-to-minute basis. Therefore, by regulating the number of functional 5-HT3 receptors associated with the membrane of gastric vagal afferent neurons, extracellular glucose is able to adapt its own ‘perception’, allowing for amplification and prolongation of its own signaling. While exposure to a HFD does not affect either the proportion of gastric vagal afferent neurons that respond to 5-HT, or the magnitude of the 5-HT-induced response, the ability of glucose to modulate 5-HT3 receptor density and function is disrupted, even after relatively short periods of HFD exposure, well in advance of the development of obesity or dysregulation of blood glucose levels, suggesting that diet may profoundly affect vagal afferent responsiveness independent of obesity. While short periods of HFD exposure disrupt and attenuate the ability of glucose to modulate 5-HT-mediated vagal signaling, restoration of a normal diet permits recovery although the time-scale for recovery appears to be much longer than that required to induce the initial reduced sensitivity. This provides additional support for the concept that vago-vagal neurocircuits are sensitive to diet-induced modulation and adaptation. Furthermore, the reversibility of the adverse effects of HFD exposure suggests that peripheral vagal afferents may be a more readily accessible and attractive target for obesity research, potentially opening the door to new treatment options and preventative techniques.