Early postnatal overnutrition: Potential roles of gastrointestinal vagal afferents and brain-derived neurotrophic factor

Abstract

Abnormal perinatal nutrition (APN) results in a predisposition to develop obesity and the metabolic syndrome and thus may contribute to the prevalence of these disorders. Obesity, including that which develops in organisms exposed to APN, has been associated with increased meal size. Vagal afferents of the gastrointestinal (GI) tract contribute to regulation of meal size by transmitting satiation signals from gut-to-brain. Consequently, APN could increase meal size by altering this signaling, possibly through changes in expression of factors that control vagal afferent development or function. Here two studies that addressed these possibilities are reviewed. First, meal patterns, meal microstructure, and the structure and density of vagal afferents that innervate the intestine were examined in mice that experienced early postnatal overnutrition (EPO). These studies provided little evidence for EPO effects on vagal afferents as it did not alter meal size or vagal afferent density or structure. However, these mice exhibited modest hyperphagia due to a satiety deficit. In parallel, the possibility that brain-derived neurotrophic factor (BDNF) could mediate APN effects on vagal afferent development was investigated. Brain-derived neurotrophic factor was a strong candidate because APN alters BDNF levels in some tissues and BDNF knockout disrupts development of vagal sensory innervation of the GI tract. Surprisingly, smooth muscle-specific BDNF knockout resulted in early-onset obesity and hyperphagia due to increases in meal size and frequency. Microstructure analysis revealed decreased decay of intake rate during a meal in knockouts, suggesting loss of vagal negative feedback contributed to their increase in meal size. However, meal-induced c-Fos activation within the dorsal vagal complex suggested this effect could be due to augmentation of vago-vagal reflexes. A model is proposed to explain how high-fat diet consumption produces increased obesity in organisms exposed to APN, and may be required to reveal effects of EPO on vagal function.

Stimulation of synthesis and release of brain‐derived neurotropic factor from intestinal smooth muscle cells by substance P and pituitary adenylate cyclase‐activating peptide

“…In histological section and in cultures of SMCs derived from intestinal smooth muscle, BDNF mRNA and protein were much more prevalent in the longitudinal layer. There are very few studies of BDNF in gut smooth muscle, however, recent studies indicate that BDNF expression in gut smooth muscle is important to the development of vagal sensory innervation . Interestingly, conditional knockout of BDNF in intestinal smooth muscle of mice resulted in enhanced innervation by vagal sensory neurons.…”

“…There are very few studies of BDNF in gut smooth muscle, however, recent studies indicate that BDNF expression in gut smooth muscle is important to the development of vagal sensory innervation. [5][6][7] Interestingly, conditional knockout of BDNF in intestinal smooth muscle of mice resulted in enhanced innervation by vagal sensory neurons. This is reflected in increased intraganglionic laminar endings of these neurons in myenteric ganglia and increased numbers of axon bundles in the longitudinal orientation.…”

“…1). Brain-derived neurotrophic factor is also present in the gut where it is found in smooth muscle of the muscularis externa and gut vasculature, [2][3][4][5][6][7][8] epithelial and enteroendocrine cells of the mucosa, 3,[8][9][10][11][12][13] and enteric neurons and glia. [8][9][10][11][12][13][14][15][16] In the gut, BDNF has also been shown to have important roles in augmenting the peristaltic reflex by enhancing serotonin (5-HT) and CGRP (calcitonin gene-related peptide) release from enteroendocrine cells and enteric sensory neurons, respectively, 9,10 in augmenting calcium responses in enteric neurons elicited by neurotransmitters thereby enhancing synaptic communication within the enteric nervous system, 11 increasing colonic myoelectrical activity, 17 and enhancing the response of SMCs to contractile agonists.…”

Role of astroglia in diet-induced central neuroplasticity

“…The DMV sends cholinergic projections to the postganglionic neurons in the myenteric plexus, which makes up two distinct pathways, the excitatory cholinergic and inhibitory nonadrenergic, noncholinergic pathway (Travagli and Anselmi 2016). Diet-induced modulation of GI vagal pathways are apparent in response to both acute and chronic exposure (Bhagat et al 2015;Clyburn et al 2018;de Lartigue et al 2011;Fox and Biddinger 2012;Kentish et al 2012Kentish et al , 2016Nefti et al 2009). DIO is associated with a decreased intrinsic excitability of vagal afferent sensory neurons and fibers (Daly et al 2011) as well as vagal efferent motoneurons, including decreasing the responsiveness to classical satiety peptides such as cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and leptin, as well as the glucose-dependent facilitation of serotonin (5-HT)-mediated responses (Bhagat et al 2015;Covasa and Ritter 2000;Duca et al 2013;Troy et al 2016).…”

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

“…The perinatal period is critical in the development of autonomic neurocircuits required for homeostatic regulation of many visceral functions including feeding and digestion, and alterations in this regulatory pathway may lead to obesity and its associated comorbidities . Vagal autonomic neurocircuits are largely responsible for relaying sensory and motor gastrointestinal (GI) information to and from the brainstem and have the ability to regulate gastric motility and emptying, indirectly influencing meal size, nutrient digestion and absorption, and energy homeostasis .…”