Homeostatic Regulation of Caloric Intake Following High Fat Diet Exposure
Open Access
- Author:
- Clyburn, Courtney
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 26, 2020
- Committee Members:
- Kirsteen Nairn Browning, Dissertation Advisor/Co-Advisor
Kirsteen Nairn Browning, Committee Chair/Co-Chair
Renato A Travagli, Committee Member
Amy Christine Arnold, Committee Member
Charles H Lang, Outside Member
Andras Hajnal, Committee Member
Alistair J Barber, Program Head/Chair - Keywords:
- High fat diet
obesity
brainstem
dorsal motor nucleus of the vagus
vagus
synaptic transmission
glutamate
plasticity
astrocyte
NMDA receptors
brain-gut axis - Abstract:
- Obesity is a rapidly growing worldwide health concern estimated to affect more than one-third of adults in the United States alone. The recent dramatic rise in diet-induced obesity (DIO) and its comorbid disorders, including type II diabetes, hypertension, and heart disease, has underscored the importance of understanding the neural mechanisms involved in energy homeostasis and visceral functions such as feeding and digestion. DIO and long-term high fat diet (HFD) exposure are associated with the dysregulation of autonomic neurocircuits including those regulating gastric functions leading to an increase in compliance of the stomach, resulting in a larger volume of food required to signal satiation. Previous studies have shown that increased body weight and adiposity can induce both peripheral and central neuroinflammation, resulting in reactive gliosis and astrocyte activation that may contribute to dysregulation of neuronal functions throughout the central nervous system (CNS), including those areas of the brainstem that contribute to the control of gastric functions. Interestingly, following acute exposure to HFD, a brief period of hyperphagia (24hrs) is followed by restoration of caloric balance and regulation of food intake. This period of homeostasis is associated with rapid reactive gliosis in the hypothalamus, even in the absence of peripheral inflammation. This finding suggests that the observed acute central inflammation may be important in the neural regulation of food intake and energy homeostasis as well as raises questions regarding whether reactive gliosis also occurs in the brainstem. Although the motoneurons of the dorsal motor nucleus of the vagus (DMV) that provide the vagal efferent innervation to the gastrointestinal tract are known to be under tonic inhibitory control by GABAergic synaptic inputs, evidence suggests that astrocyte activation and rapid alterations in neuronal excitability are frequently associated with alterations in excitatory, glutamatergic, signaling. The effects of short periods of HFD exposure on excitatory brainstem vagal neurocircuits involved in the regulation of gastric functions, however, have yet to be determined. The overarching hypothesis of this dissertation is that acute periods of HFD exposure induce the activation of brainstem astroglia that subsequently modulate excitatory synaptic signaling in central vagal neurocircuits resulting in the regulation of caloric intake. This multilayered research study uses several experimental approaches (e.g. whole-cell patch clamp electrophysiology recordings from identified DMV neurons in thin brainstem slices, and in vivo measurement of gastric tone, motility, emptying, and compliance) to investigate the neural mechanisms involved in the regulation of caloric intake and how disruption of this mechanism may affect gastric functions and energy homeostasis. The principle findings of the present studies describe the neuroplasticity responsible for the regulation of caloric intake. In summary, following acute HFD exposure and during the homeostatic regulation of caloric intake 1) DMV synaptic N-methyl-D-aspartate receptors (NMDARs) are activated to increase neuronal excitability, 2) activation of extrasynaptic NMDAR (NMDARex) causes a local membrane depolarization sufficient to remove the voltage dependent magnesium block of NMDARs and allow their activation, and is required for the restoration of caloric balance and, 3) activation of brainstem astrocytes is required for the activation of NMDARex, possibly via mechanisms that involve the release of gliotransmitters. In total, the neuroplasticity described in the present studies suggest that an increase in the excitatory glutamatergic drive to DMV neurons is responsible for the alterations in DMV neuronal excitability, efferent output, and gastric motility, which decreases food intake and restores caloric balance following acute HFD exposure. Understanding the plasticity in brainstem neurocircuitry resulting from alterations in nutrition brings insight to the mechanistic basis for the homeostatic regulation of feeding behavior by brain-gut neurocircuits. A deeper understanding of how and why the dysregulation of these pathways leads to impaired energy balance and hyperphagia will be critical to the development of novel therapeutic strategies and the identification of potential pharmacological targets for the treatment of obesity.