Diet‐induced obesity has neuroprotective effects in murine gastric enteric nervous system: involvement of leptin and glial cell line‐derived neurotrophic factor

Abstract

Non-technical summary The enteric nervous system (ENS) is an autonomous nervous system integrated along the gut that controls major gastrointestinal (GI) functions such as motility. Increasing data have demonstrated that nutritional factors can modulate the ENS phenotype and consequently impact upon GI functions. Western diet is central in the development of obesity but surprisingly no study has characterized its impact upon ENS phenotype and functions. We show that Western diet-induced obesity (DIO) prevented age-associated loss in a specific population of enteric neurons leading to an acceleration of gastric emptying. In addition, we showed that neuroprotective effects of DIO likely involved leptin and glial cell line-derived neurotrophic factor (GDNF). This is the first study demonstrating an impact of DIO upon the ENS. These DIO-induced neuroplastic changes in the ENS could be involved in the physiopathology of obesity.Abstract Nutritional factors can induce profound neuroplastic changes in the enteric nervous system (ENS), responsible for changes in gastrointestinal (GI) motility. However, long-term effects of a nutritional imbalance leading to obesity, such as Western diet (WD), upon ENS phenotype and control of GI motility remain unknown. Therefore, we investigated the effects of WD-induced obesity (DIO) on ENS phenotype and function as well as factors involved in functional plasticity. Mice were fed with normal diet (ND) or WD for 12 weeks. GI motility was assessed in vivo and ex vivo. Myenteric neurons and glia were analysed with immunohistochemical methods using antibodies against Hu, neuronal nitric oxide synthase (nNOS), Sox-10 and with calcium imaging techniques. Leptin and glial cell line-derived neurotrophic factor (GDNF) were studied using immunohistochemical, biochemical or PCR methods in mice and primary culture of ENS. DIO prevented the age-associated decrease in antral nitrergic neurons observed in ND mice. Nerve stimulation evoked a stronger neuronal Ca 2+ response in WD compared to ND mice. DIO induced an NO-dependent increase in gastric emptying and neuromuscular transmission in the antrum without any change in small intestinal transit. During WD but not ND, a time-dependent increase in leptin and GDNF occurred in the antrum. Finally, we showed that leptin increased GDNF production in the ENS and induced neuroprotective effects mediated in part by GDNF. These results demonstrate that DIO induces neuroplastic changes in the antrum leading to an NO-dependent acceleration of gastric emptying. In addition, DIO induced neuroplasticity in the ENS is likely to involve leptin and GDNF.

High-Fat Diet-Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms

“…The reports are inconsistent with reports of no difference (Buchholz et al, 2013), increased (Baudry et al, 2012), and decreased rates of gastric emptying (Kentish et al, 2015). There are no studies that have addressed whether the circadian pattern of gastric emptying is altered in obesity.…”

Emerging roles for enteric glia in gastrointestinal disorders

“…Studies of aging reveal a consistent reduction in enteric glial cell density in the myenteric plexus (28,44). In contrast, the development of obesity caused by feeding a high-fat diet had only minimal effects on glial cell density in the myenteric plexus but did lead to a massive reduction in apparent glial cell density in the duodenal mucosa and the submucosal plexus (45). Interestingly, food restriction in aging rats actually accentuated the loss of enteric glia, although it had been expected that food restriction may reduce the parameters of oxidative stress in the GI tract (46).…”

“…However, studies examining the effects of dietary manipulation and aging reveal that enteric glial cell numbers appear to be influenced by both age and diet, suggesting that environmental factors are able to influence glial cell numbers (28,(42)(43)(44)(45)(46). Studies of aging reveal a consistent reduction in enteric glial cell density in the myenteric plexus (28,44).…”

Le système nerveux entérique et l’unité neuro-glio-épithéliale digestive

“…L'évolution du SNE au cours du jeune âge et de l'adolescence reste en revanche encore mal connue. Des données récentes suggèrent qu'il existe dans l'estomac, mais non dans l'intestin (jéju-num), une perte neuronale associée à un ralentissement « physiologique » de la vidange gastrique (Baudry et al 2012). Au cours du vieillissement, une perte neuronale a été mise en évi-…”