Connecting a Western diet, palmitic acid, and enteric neuropathy
Rexford S. Ahima
Rexford S. Ahima
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Connecting a Western diet, palmitic acid, and enteric neuropathy

Abstract

The Western diet (WD) is a rich source of saturated fatty acids, especially palmitic acid (PA), which has been implicated in the pathogenesis of insulin resistance, oxidative stress, inflammation, diabetes, and multiorgan dysfunction in obesity and diabetes. In this issue of the JCI, a study by Balasubramaniam et al. describes mechanisms linking a WD, PA, ferroptosis (iron-dependent cell death), and loss of colonic motility. Chronic PA exposure drove ferroptosis in murine in vitro systems and human myenteric ganglia. Mice fed a WD for 12 weeks developed enteropathy and loss of colonic motility, which was reversed by adeno-associated virus–mediated (AAV-mediated) overexpression of the transcription factor NFE2L2, preventing ferroptosis and restoring redox balance to enteric neurons. The study provides critical data establishing PA-induced ferroptosis as a mediator and potential therapeutic target in enteric nervous system disorders associated with obesity.

Authors

Rexford S. Ahima

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Figure 1

ENS dysfunction in diet-induced obesity.

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ENS dysfunction in diet-induced obesity. (A) Innervation of the GI tract...
(A) Innervation of the GI tract. Schematic showing the extrinsic ANS and the intrinsic ENS. Sympathetic (blue) and parasympathetic (pink) fibers originate from the CNS and synapse with the ENS within the myenteric and submucosal plexus to regulate gut motility, secretion, vascular function, and interactions with the immune system and gut microbiota. (B) Balasubramaniam et al. (8) connected consumption of a Western HFD to loss of enteric neurons and gut motility. HFD consumption resulted in elevated saturated fatty acids, specifically PA, which promoted increased iron influx into enteric neurons, leading to iron overload. This excess iron, combined with PA, reduced glutathione (GSH) levels and inhibited the activity of GPX4, a critical inhibitor of lipid peroxidation. Consequently, elevated free iron levels and lipid peroxidation caused mitochondrial dysfunction and increased ROS production, enteric neuronal death (ferroptosis), and reactive gliosis, culminating in enteric neuropathy and impairment of colonic motility.