OBESITY AND ENTERIC NERVOUS SYSTEM MODULATION: EVIDENCE FROM PRECLINICAL ANIMAL MODELS

Nutrient absorption and energy metabolism are regulated by the enteric nervous system (ENS), which thereby controls the onset of obesity. In addition, the interplay between obesity and cognitive dysfunction via the gut-brain axis has been reported. Since we have already assessed central nervous system alterations in obese animals, the current study will aim at providing the long-term effects of obesity upon the ENS in male diet-induced obesity (DIO) rats and leptin receptor-deficient obese Zucker rats (OZRs). DIO rats developed obesity after five weeks of alimentation with a highfat diet (HFD), and they used the same diet for further 12 weeks. Control animals (CHOW) were fed a normal diet. Both DIO and OZRs had a significant increase in body weight and systolic blood pressure compared to the CHOW and lean Zucker rats (LZRs), respectively. The assessment of blood parameters showed that glycemia and insulin levels were higher in both obese models in comparison to controls. Contrary to OZRs, no difference in total cholesterol and triglycerides levels were found in DIO rats. Immunochemical and immunohistochemical techniques were performed in distinct portions of the small and large intestines. Sections were stained with anti-HuC/D (for evaluating the neural network) and anti-GFAP (for identifying astrocytes). Concerning the results in obese conditions, myenteric neurons showed a reduction of HuC/D staining especially, in the jejunum as well as in the distal colon, suggesting neuronal degeneration associated with obesity. The GFAP level did not change in the small intestine of DIO animals. Vice versa, a slight alteration was reported in OZRs. Conversely, a reduction of glial immunoreaction in the myenteric plexus of the distal colon was observed in obese animals, which may be attributed to lipotoxicity. Damages to the enteric glia could also affect the integrity of enteric neurons. Moreover, the network of vesicular acetylcholine transporter (VAChT)-positive fibers and cell bodies were more evident in the intestine of obese rats than in lean controls. Additionally, this change was accompanied by mildly intestinal inflammation. These findings suggest that obesity caused alterations of myenteric neurons and glial cells that could delay motility control, intestinal barrier function, and secretion.