Abstract
Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3–5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor–mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor–mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.
Highlights
The rates of obesity and its comorbid disorders, including hypertension, type 2 diabetes, and heart disease, have been increasing dramatically in the United States and worldwide [1], highlighting the importance of understanding the neural mechanisms involved in the regulation of visceral functions, such as feeding and digestion
The results from the present study suggest that after Acute high-fat diet (aHFD) exposure, activation of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) 1) is required for the activation of synaptic NMDAR–dependent currents and the preservation of gastric-projecting dorsal motor nucleus of the vagus (DMV) neuronal excitability; 2) is responsible for the synaptic NMDAR modulation of vagally dependent gastric tone, motility, and emptying; and 3) results in the homeostatic regulation of caloric intake
Studies in human and animal models have shown that a brief (24 hour) period of hyperphagia occurs in response to high-fat diet (HFD) exposure, which is followed by a decrease in food intake and the restoration of caloric balance within 3 to 5 days [14,15,16,17]
Summary
The rates of obesity and its comorbid disorders, including hypertension, type 2 diabetes, and heart disease, have been increasing dramatically in the United States and worldwide [1], highlighting the importance of understanding the neural mechanisms involved in the regulation of visceral functions, such as feeding and digestion. Sensory inputs from the stomach and upper GI tract transmit chemical and mechanical information through vagal afferent fibers to the neurons of the nucleus tractus solitarius The NTS integrates this sensory signal with inputs from the brainstem and hypothalamus involved in energy regulation and sends either glutamatergic, GABAergic, or catecholaminergic projections to the adjacent dorsal motor nucleus of the vagus (DMV). The DMV provides parasympathetic efferent (motor) output to the stomach and upper GI tract to coordinate gastric functions, food intake, and energy homeostasis. The DMV provides parasympathetic efferent (motor) output to the stomach and upper GI tract to coordinate gastric functions, food intake, and energy homeostasis. [6, 7]
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