Exposure to a high fat diet during the perinatal period alters vagal motoneurone excitability, even in the absence of obesity

Abstract

Key pointsr Obesity is recognized as being multifactorial in origin, involving both genetic and environmental factors. The perinatal period is known to be critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes.r Diet-induced obesity alters the biophysical, pharmacological and morphological properties of vagal neurocircuits regulating upper gastrointestinal tract functions, including satiety. Less information is available, however, regarding the effects of a high fat diet (HFD) itself on the properties of vagal neurocircuits.r The present study was designed to test the hypothesis that exposure to a HFD during the perinatal period alters the electrophysiological, pharmacological and morphological properties of vagal efferent motoneurones innervating the stomach.r Our data indicate that perinatal HFD decreases the excitability of gastric-projecting dorsal motor nucleus neurones and dysregulates neurotransmitter release from synaptic inputs and that these alterations occur prior to the development of obesity. These findings represent the first direct evidence that exposure to a HFD modulates the processing of central vagal neurocircuits even in the absence of obesity.Abstract The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet-induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric-projecting DMV neurones in thin brainstem slices from rats that were exposed to either a control diet or HFD from pregnancy day 13. Our data demonstrate that following perinatal HFD: (i) DMV neurones had decreased excitability and input resistance with a reduced ability to fire action potentials; (ii) the proportion of DMV neurones excited by cholecystokinin (CCK) was unaltered but the proportion of neurones in which CCK increased excitatory glutamatergic synaptic inputs was reduced; (iii) the tonic activation of presynaptic group II metabotropic glutamate receptors on inhibitory nerve terminals was attenuated, allowing modulation of GABAergic synaptic transmission; and (iv) the size and dendritic arborization of gastric-projecting DMV neurones was increased. These results suggest that perinatal HFD exposure compromises the excitability and responsiveness of gastric-projecting DMV neurones, even in the absence of obesity, suggesting that attenuation of vago-vagal reflex signalling may precede the development of obesity.

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

“…Although hypothalamic regulation has always been viewed as the master controller of body weight, we cannot discount the importance of other central regions, including the brainstem. A recent study showed that exposure to HF during the perinatal period compromises the excitability and responsiveness of the gastric-projecting dorsal motor nucleus of the vagus (Bhagat et al 2015). Furthermore, lateral pontine parabrachial nucleus leptin receptor activation leads to reduced food intake (Alhadeff et al 2014).…”

Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions

“…While many of these alterations, including decreased neuronal excitability and input resistance and increased soma size, are intrinsic to the DMV neuronal membrane themselves, we also observed changes in the ability of neuroendocrine hormones such as CCK to modulate synaptic transmission, suggesting diet‐induced changes at the presynaptic level. Of interest, the tonic activation of presynaptic group II metabotropic receptors on inhibitory inputs within vagal neurocircuits is attenuated following PNHFD, allowing modulation of previously silent GABAergic synapses . This altered response may be directly related to a high fat diet‐induced alteration in vagal afferent responsiveness which normally tonically decrease the state of activation of inhibitory terminals within the brainstem .…”

“…Thus, while this study suggests that DMV neurons, and vagally‐dependent gastric functions, from PNHFD rats are under a greater degree of tonic synaptic inhibition, the nature of this increased inhibition remains to be determined. The diet used in this study, in which 60% kcal are derived from fat, is used commonly in many perinatal dietary studies including our own . Clearly, however, that the fat content of this diet is excessive, and future studies assessing whether similar results are obtained following perinatal exposure to the more “western diet” (35%‐40% kcal from fat) would be important from a translational point of view.…”

“…Previous studies have demonstrated that exposure to a high fat diet (HFD), or diet‐induced obesity, decreases vagal afferent sensitivity and attenuates the sensory limb of vago‐vagal GI reflexes and also decreases the excitability of vagal efferent motoneurons . Little attention has been paid, however, to the developmental effects of HFD exposure on vagal neurocircuits regulating GI functions, although we have demonstrated previously that the influential tonic GABAergic input onto DMV neurons may be affected by PNHFD exposure …”

Developmental specification of metabolic circuitry

“…The observation that mice exposed to a maternal high fat diet show reduced parasympathetic innervation of the pancreas, which originates at the level of the DMX (Vogt et al, 2014) is consistant with the notion that nutritional programming early in life might impart permanent effects on this circuitry. Rat pups exposed to a similar postnatal manipulation show perturbations in the overall excitability and morphology of DMX neurons that project to the stomach, as well as a reduced responsiveness to CCK at the level of the NTS (Bhagat et al, 2015). These studies show how alterations in perinatal nutrition may impact development of DVC circuitry.…”