Alarming evidence: high fat diet alters brainstem circuits prior to the development of obesity.

Abstract

The prevalence of obesity and its associated diseases, including type 2 diabetes mellitus, has substantially increased worldwide, placing a significant burden both on individuals and society as a whole. This healthcare crisis requires the development of novel interventions and effective obesity prevention strategies. Alarmingly, numerous recent studies have emphasized the importance of gestational and perinatal periods, which have a critical influence on the offspring's weight and metabolism in the development of obesity (Kubo et al. 2014; Sullivan & Grove 2010; Sullivan et al. 2011). Considering the high incidence of obesity in the general population, including women of child-bearing age, studies investigating the effect of overnutrition and a high fat diet (HFD) during gestational and perinatal periods on the health of offspring have particular relevance and importance for global health and economy. It has been demonstrated that maternal hyperglycaemia or gestational diabetes is associated with a higher risk of childhood obesity and this risk increases if the mother is overweight or obese (Kubo et al. 2014). Studies using rodent models showed that maternal HFD consumption or overnutrition contributes to the development of hyperphagia (Sullivan et al. 2011). Upregulation of orexigenic peptides, decreased sensitivity to leptin, and abnormalities of the central melanocortin, serotonin and dopamine systems have also been reported and associated with maternal HFD consumption (Chang et al. 2008; Sullivan & Grove, 2010; Sullivan et al. 2011). These findings have been linked to changes in hypothalamic pathways controlling feeding circuits and disruption of these circuits contributes to the development of obesity. The hypothalamus works in concert with brainstem autonomic centres to maintain homeostatic functions. A variety of studies have demonstrated that diet-induced obesity causes multiple changes in vagal neural circuits, which compromise the function of both the vagal afferents and efferents; however, in these studies it is difficult to differentiate the effect of diet and/or obesity. Therefore, the following question arises: does HFD alone modulate vagal neural circuits and if it does, when do the changes occur? Previous studies demonstrated the vulnerability of the brainstem autonomic neural circuits to exposure to HFD and postulated that HFD dysregulates the vagal reflex control independently of obesity (Covasa & Ritter, 2000; Swartz et al. 2010; Browning et al. 2013); however, direct evidence demonstrating the effect of perinatal HFD on neuronal excitability remained unknown. Bhagat and his coworkers have designed an elegant study, reported in this issue of The Journal of Physiology (Bhagat et al. 2015), to investigate the consequences of perinatal HFD consumption on vagal motor neurons using electrophysiological, pharmacological and morphological approaches. Their study focuses on gastric-related motor neurons and demonstrates that perinatal HFD consumption dysregulates neurotransmitter release from synaptic inputs and reduces the excitability of gastric-projecting neurons in the dorsal motor nucleus of the vagus. These changes were accompanied by increased size and dendritic arborization of gastric-projecting vagal motor neurons, and were observed prior to the development of obesity. The observation that the changes occur before the development of obesity gives a particular importance to these novel findings, because it points out that the attenuation of the vago-vagal reflex signalling exists before the development of obesity. In agreement with previous findings that show the vulnerability of autonomic circuits, the authors’ data demonstrate that the perinatal period is a critical time, which may determine the weight and/or metabolism of the offspring. On the other hand, further studies are needed to establish the particular time frame (e.g. in utero or pre-weaning phrases) responsible for these changes to answer the question: are these changes in vagal neural circuits caused by perinatal HFD exposure reversible or not, and what are the underlying mechanisms? Taken together, increasing evidence, including the current study by Bhagat et al., demonstrates that maternal and perinatal diet has a significant effect on the central nervous system, including the autonomic pathways that regulate homeostatic functions. Furthermore, these changes in vagal circuitry may define the susceptibility to obesity and metabolic disorders; however, further detailed studies are needed to delineate the underlying mechanisms.