Neural Mechanisms Responsible for the Regulation of Caloric Intake Following Acute High Fat Diet are Developmentally Regulated

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Previous studies have shown that, in adulthood, acute high fat diet (HFD) exposure is associated with an initial period of hyperphagia before caloric intake is restored within 3–5 days. This period of homeostasis is accompanied by activation of NMDA receptors (NMDA‐R) and increased excitability of identified vagal efferent motoneurons regulating gastric motility. The mechanisms responsible regulation of caloric intake, as well as how and why these mechanisms are lost, are critical to understanding the development of obesity. Alterations in vagal neurocircuit maturation following perinatal (p)HFD exposure, has profound effects on neural control of gastric motility in adulthood, including the failure to regulate caloric intake, which may increase the predisposition to develop obesity. Our previous studies have shown that, following pHFD, inhibitory synaptic inputs to vagal efferent motoneurons are increased, which may prevent the voltage‐dependent activation of synaptic NMDA‐Rs. The purpose of this study was to test the hypothesis that pHFD exposure attenuates the homeostatic activation of DMV NMDA‐Rs following acute HFD exposure in adulthood, leading to dysregulated gastric motility.Sprague Dawley rats were exposed to a control or HFD (14% or 60% kcal from fat, respectively) during postnatal (P) days 1–10. In adulthood, (>P28) rats were re‐exposed to a HFD for 3–5 days prior to experimentation. Whole‐cell patch clamp recordings were made from DMV neurons and the effects of the NMDA‐R antagonist, AP5 (25μM) was tested on miniature excitatory postsynaptic current (mEPSC) amplitude and action potential (AP) firing rates. The 13C octanoic acid breath test was used to determine the effects of pHFD (P1–10) exposure on basal gastric emptying rates. Food intake and body weight was measured twice daily for 10 days prior to, and throughout, adult exposure to HFD.pHFD (P1–10) exposure attenuated the actions of AP5 to inhibit DMV NMDA‐R activation (mEPSC amplitude: 103±5.7% vs. 35±9.4%, P<0.05, N=4–6), and to decrease neuronal excitability (AP firing rate: 102±7.7% vs. 21±13.7% of baseline, P<0.05; N=4–7) observed previously following acute HFD exposure in adulthood. Measurement of gastric emptying rates suggest that pHFD exposure itself significantly delayed baseline gastric emptying (73±1.4 vs. 63±4.3min, P<0.05 N=8–12), and, unlike control rats, gastric emptying was not delayed further by adult dietary challenge (102±13.0% vs. 144±15.8% of baseline, respectively, P>0.05, N=4–6). Additionally, rats that were exposed to a pHFD (P1–10) did not regulate their caloric intake within 3–5 days of adult HFD exposure, as observed control rats (AUC: 215±28.0 vs. 393±34.7, P<0.05, N=9–16).These data suggest that pHFD (P1–10) exposure disrupts central vagal neurocircuit development, increasing the inhibitory drive to DMV neurons, delaying gastric emptying, and preventing the homeostatic regulation of gastric emptying and caloric intake in response to acute adult HFD exposure. Understanding how diet affects the development of vagal neurocircuits is critical for identifying therapeutic targets for the development of obesity.Support or Funding InformationNIH DK111667 to KNB NIH F31 118833 to CC