Astroglial Modulation of Glutamatergic Currents in Neurons of the Dorsal Motor Nucleus of the Vagus Following Acute High‐Fat Diet Exposure

Abstract

Exposure to high fat diet (HFD) and diet‐induced obesity (DIO) have a strong association with inflammation. Neuroinflammation and astroglial activation modulates neuronal activity through several mechanisms, including modulation of glutamatergic transmission. We have shown recently that acute (3–5 days) HFD exposure modulates glutamatergic transmission to motoneurons of the dorsal motor nucleus of the vagus (DMV) through activation of the synaptic NMDA receptor (NMDA‐R), which increases motoneuron excitability and gastric motility (PMID: 29368945). The purpose of this study is to test the hypothesis that astroglial activation increases the glutamatergic drive to neurons of the DMV resulting in the regulation of gastric functions.Whole‐cell patch clamp recordings were made from gastric‐projecting DMV neurons in thin (300μm) brainstem slices of Sprague‐Dawley rats, 4–6 weeks of age. Rats were fed a control diet (14% kcal from fat), or an HFD (60% kcal from fat) for 3–5 days prior to experimentation. The effects of the astrocyte metabolism inhibitor, fluoroacetate (100mM) on glutamate‐mediated miniature excitatory postsynaptic current (mEPSC) kinetics were examined. Food intake was measured twice daily throughout exposure to HFD. An additional group of rats (n=6; 5 weeks of age) were fitted with a 4th ventricular cannula for the chronic administration of fluoroacetate (10mg/2mL) or vehicle (phosphate‐buffered solution; PBS) and gastric emptying was measured using the 13C octanoic acid breath test. Rats were trained to eat a pancake treated with 13C octanoic acid. After habituation, rats were fasted overnight (water ad libitum) and baseline GE rates were measured twice before rats were switched to an HFD for 9 days, with GE measured on days 1,4 and 9 following HFD exposure.Fluoroacetate, had no effect in control rats but decreased mEPSC amplitude and frequency following acute HFD (98.6±3% vs. 73.0±4% and 78.8±6% vs. 53.9±11% of baseline, respectively, n=12–13 P<0.05). The GE rates of rats was delayed significantly 4 days after HFD exposure (t1/2 64±4.5 vs 89±0.1min for control vs. HFD, n=8 P<0.05) corresponding to the regulation of caloric intake (59±3.7 vs. 55±6.9 kcal/24hrs baseline vs. 4 day n=12 HFD P>0.05). By 9 days of HFD exposure, GE rates returned to baseline (t1/2 64±4.5 vs 67±1.4min for control vs. HFD, n=8 P>0.05), corresponding to the period when rats become hyperphagic (55±6.9 vs 66±2.2 kcal/24hrs baseline vs. HFD, n=12 P<0.05). Preliminary data suggests that chronic 4th ventricular administration of fluoroacetate attenuates the decrease in GE observed 4 days following HFD exposure.These data suggest that astroglial activation is involved in the acute HFD‐induced modulation of glutamatergic currents and delay in GE rates. Astroglia may be responsible for the activation of synaptic NMDA‐R and regulation of gastric functions through the release of receptor co‐agonists, such as glycine, or through release of gliotransmitters such as glutamate. Understanding the mechanism responsible for the regulation of food intake following acute exposure to HFD is critically important in identifying potential therapeutic targets for the treatment of obesity.Support or Funding InformationNIH DK111667 to KNBThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.