High-fat diet ingestion correlates with neuropathy in the duodenum myenteric plexus of obese mice with symptoms of type 2 diabetes

Abstract

Obesity and type 2 diabetes are increasing in prevalence at an alarming rate in developed and developing nations, and over 50% of patients with prolonged stages of disease experience forms of autonomic neuropathy. These patients have symptoms indicating disrupted enteric nervous system function including gastric discomfort, gastroparesis and intestinal dysmotility. Previous assessments have examined enteric neuronal injury within either type 1 diabetic or transgenic type 2 diabetic contexts. This study aimed to assess damage to myenteric neurons within the duodenum of high fat diet ingesting mice experiencing symptoms of type 2 diabetes, as this disease context is most parallel to the human condition and disrupted duodenal motility underlies negative gastrointestinal symptoms. Mice fed a high fat diet developed symptoms of obesity and diabetes by 4 weeks. After 8 weeks, the total number of duodenal myenteric neurons and synaptophysin density index were reduced and transmission electron microscopy showed axonal swelling and loss of neurofilaments and microtubules, suggesting compromised neuronal health. High fat diet ingestion correlated with a loss of neurons expressing VIP and nNOS, but did not affect the expression of ChAT, substance P, calbindin and CGRP. These results correlate high fat diet ingestion, obesity and type 2 diabetes symptoms with a loss of duodenal neurons, biasing towards those with inhibitory nature. This pathology may underlie dysmotility and other negative GI symptoms experienced by human type 2 diabetic and obese patients.

Prolonged high fat diet ingestion, obesity, and type 2 diabetes symptoms correlate with phenotypic plasticity in myenteric neurons and nerve damage in the mouse duodenum

“…HF diet-ingesting mice in the current study were previously shown to have high weight gain, epididymal adipose tissue mass, glucose intolerance and insulin resistance compared to mice ingesting a SC diet (Stenkamp-Strahm et al 2013a; Stenkamp-Strahm et al 2013b). Obesity and T2D characteristics were first identified in these mice after 4 weeks of HF diet ingestion, became more progressed at 8 weeks, and markedly progressed after 20 weeks.…”

“…Collection of duodenal segments, fixation, dissection, preservation, EM, LMMP, and cryostat tissue sample (full thickness; FT) preparations were processed as previously described (Stenkamp-Strahm et al 2013a). …”

“…Studies by our group have also shown a reduction in total duodenal myenteric neurons, including nNOS/VIP containing neurons, in mice fed a 72% high-fat (HF) diet for 8 weeks (Stenkamp-Strahm et al 2013a). It is well understood that the ENS undergoes a loss of cells in the duodenum and other segments during normal aging (El-Salhy et al 1999; Wade 2002; Stenkamp-Strahm et al 2013b).…”

High-Fat Diet Promotes Neuronal Loss in the Myenteric Plexus of the Large Intestine in Mice

“…The observed reduction may be attributable to the low expression of VIP mRNA or an increase in the release of the neurotransmitter, resulting in low reserves in the varicosities [25]. Furthermore, neurons in the small intestine in mice that were fed a HFD showed neurodegeneration, axonal swelling, and disruption of the microtubule and neurofilament network [35], which could affect the transport of neurotransmitters along axons.…”

26 Intestinal Dysbiosis Contributes to the Delayed Gastrointestinal Transit in High Fat Diet Fed Mice

“…This loss of nitrergic myenteric neurons appears to be a common feature associated with long-term, high-fat feeding. Stenkamp-Strahm et al 44 described similar loss in the duodenum of mice presenting with symptoms of diabetes after the ingestion of a HFD (72% kcal fat) for 8 weeks, but it also was described in the colon of mice fed a moderately HFD (35% fat content) for 8 and 17 weeks. 45 Similar alterations were observed in the colon of mice fed with a low-fat diet (21% fat, 2% cholesterol) for 33 weeks, which showed hepatic steatosis but no signs of diabetes.…”