THE ENTERIC NERVOUS SYSTEM IN OBESE ZUCKER RATS AS AN ANIMAL MODEL OF METABOLIC SYNDROME

The interaction between brain and gut has been long recognized. This bidirectional interaction plays an important role not only in gastrointestinal function but also in shaping higher cognitive function such as feelings and subconscious decision-making. Disturbances of this system have been associated with a wide range of disorders, including obesity. Previous studies have highlighted increased intestinal permeability and signs of intestinal inflammation both in rats and in mice with obesity induced by high-fat diet. In addition, other findings have reported neuronal plasticity in obese animals prior to the development of pathological changes in the histological features or abnormal mucosal functions. In Obese Zucker rats (OZRs) modifications in the glucidic profile of the intestinal mucosa and secretory products were found. To investigate the impact of obesity/metabolic syndrome on key intestinal functions and phenotype, we have studied the intestinal tracts of OZRs at two different age, compared to the lean control rats (LZRs). Distinct portions of the small intestine (duodenum, jejunum, and ileum) were analyzed by the immunochemical and immunohistochemical approach. Sections were treated with anti-HUCD (for studying the neural network), glial fibrillary acidic protein (GFAP) (for evaluating astrocytes elements), neuronal nitric oxide synthase (nNOS) and Vesicular acetylcholine transporter (VAChT) to characterize the different type of enteric neurons. Data on body weight showed an increase in the OZRs of different age. The blood pressure was higher in the OZRs compared to the LZRs of 20 weeks of age. The values of glucose and insulin increased in OZRs of different ages compared to the LZRs. The OZRs showed a remarkable increase in triglycerides and total cholesterol. These data indicate in OZRs a condition of dis-metabolism similarly to metabolic syndrome. Enteric neurons were detected by cytoplasmic and/or nuclear HuC/D immunostaining. In duodenum, jejunum, and ileum of 20-week old OZRs, myenteric neurons displayed an inhomogeneous HuC/D staining and several cytoplasmic vacuoles, with a scant cytoplasmic HuC/D expression. Immunoreaction with antiGFAP showed a clear localization of glial cells around the body neurons of myenteric ganglia. The reaction increased around the neurons in 20-weeks-old OZRs compared age-matched LZRs. Obesity correlates with a reduction in nNOS neurons. In fact, the section of OZRs incubated with the anti-nNos antibody, revealed a reduction of positive neurons in ganglia and reduction of nNOS reactive fibers. In OZRs, the network of VAChT-positive nerve fibers and cell bodies was more evident than in LZRs at 20 weeks of age. The above data showed that OZRs display a progressive decrease in myenteric neurons in the duodenum, jejunum, and ileum that coincides with transient inflammation of the gastrointestinal tract. These observations suggest that obese rats have altered intestinal motor control, attributable to a loss of ganglionic neurons, potentially related to the activation of astrocytes cells and inflammatory process