Abstract
Diabetes impairs enteric nervous system functions; however, ultrastructural changes underlying the pathophysiology of the myenteric plexus and the effects of sodium-glucose co-transporter (SGLT) inhibitors are poorly understood. This study aimed to investigate three-dimensional ultrastructural changes in axonal varicosities in the myenteric plexus and the effect thereon of the SGLT inhibitor phlorizin in mice fed a high-fat diet (HFD). Three-dimensional ultrastructural analysis using serial block-face imaging revealed that non-treated HFD-fed mice had fewer axonal varicosities and synaptic vesicles in the myenteric plexus than did normal diet-fed control mice. Furthermore, mitochondrial volume was increased and lysosome number decreased in the axons of non-treated HFD-fed mice when compared to those of control mice. Phlorizin treatment restored the axonal varicosities and organelles in HFD-fed mice. Although HFD did not affect the immunolocalisation of PGP9.5, it reduced synaptophysin immunostaining in the myenteric plexus, which was restored by phlorizin treatment. These results suggest that impairment of the axonal varicosities and their synaptic vesicles underlies the damage to the enteric neurons caused by HFD feeding. SGLT inhibitor treatment could restore axonal varicosities and organelles, which may lead to improved gastrointestinal functions in HFD-induced obesity as well as diabetes.
Highlights
The enteric nervous system (ENS) is mainly composed of the myenteric and the submucosal plexus, the former of which is located between the longitudinal and circular smooth muscle layers, and regulates the physiological functions of the gastrointestinal tract[1]
These results demonstrated that the onset of obesity/overweight occurred at 4–16 weeks of High-fat diet (HFD) intake and was accompanied by an increase in the blood glucose level, which was ameliorated by PLZ treatment
We used a mouse model of prediabetes established by long-term consumption of an HFD to analyse changes in neuronal processes and the effect of an sodium-glucose co-transporter (SGLT) inhibitor on neurons in the myenteric plexus. 3D ultrastructural analyses of the myenteric plexus revealed that the axons in HFD-Veh mice had fewer varicosities and collateral branches when compared with those in standard diet (STD)-Veh mice
Summary
The enteric nervous system (ENS) is mainly composed of the myenteric and the submucosal plexus, the former of which is located between the longitudinal and circular smooth muscle layers, and regulates the physiological functions of the gastrointestinal tract[1]. An HFD has been found to increase ROS production and reduce antioxidant enzyme activities, with a concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission[10] These results suggest that mitochondrial damage and dysfunction may play a role in the dying-back neurodegeneration that occurs in diabetic neuropathy. The above studies suggested that increased dietary fat predisposes animals to nerve dysfunction even in the absence of T2DM Whether such neurological changes occur in the autonomic nerves of the intestinal tract in response to an HFD remains unknown, and the longstanding structural changes in the myenteric plexus caused by HFD have not been fully characterised via detailed ultrastructural a nalyses[11]. Little is known about the effect of SGLT inhibitors on the myenteric plexus in HFD-induced obesity as well as diabetes. We evaluated the effect thereon of an SGLT inhibitor, phlorizin (PLZ), via immunohistochemistry and 3D ultrastructural analyses
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