Obesity and Age-Related Changes in the Brain of the Zucker Lepr(fa/fa) Rats

Metabolic syndrome (MetS) is an association between obesity, dyslipidemia, hyperglycemia, hypertension and insulin resistance. A relationship between MetS and vascular dementia was hypothesized. This study has investigated brain microanatomy in obese Zucker rats (OZRs), as a model of obesity and type-2 diabetes, compared to their lean counterparts Zucker rats (LZRs). The purpose of this work was to determine the correlation between MetS and brain injury. 12-, 16- and 20-weeks-old male OZRs and LZRs were studied. General physiological parameters and blood values were measured. Immunochemical and immunohistochemical techniques were applied to analyze the brain alterations. The morphology of nerve cells and axons, astrocytes and microglia were investigated. The blood-brain barrier (BBB) changes occurring in OZRs were assessed as well, using aquaporin-4 (AQP4) and glucose transporter protein-1 (GLUT1) as markers. Bodyweight gain, hypertension, hyperglycemia, and hyperlipidemia were found in OZRs compared to LZRs. In the frontal cortex and hippocampus, a decrease of neurons was noticeable in the older obese rats in comparison to their age-matched lean counterparts. In OZRs, a reduction of neurofilament immunoreaction and gliosis were observed. The BBB of older OZRs revealed an increased expression of AQP4 likely related to the development of oedema. A down-regulation of GLUT1 was found in OZRs of 12 weeks of age, whereas it increased in older OZRs. The behavioural analysis revealed cognitive alterations in 20-week-old OZRs. Based on these results, the OZRs may be useful for understanding the mechanisms through which obesity and related type 2 diabetes mellitus induce neurodegeneration.