Obesity affects central nervous system: a multidisciplinary study in Diet-Induced Obesity (DIO) rats

Obesity has doubled worldwide in the last thirty years, becoming pandemic [1]. Overconsumption of energy-dense food is advanced as the major explanation for the current increase of overweight and obesity, including for children and adolescents [2]. Obesity represents also an independent risk factor for the development of cerebrovascular disease and cognitive impairment. The systemic effects, such as increased fat mass, hypertension, insulin resistance and general metabolic dysfunction, have been identified as factors that may lead to im-paired cognitive function [3]. In humans, obesity is associated with cognitive deficits, especially de-clarative memory which depends on the hippocampus [4]. To clarify the possible relationships between obesity and nervous system changes, high-caloric Diet-Induced Obesity (DIO) rats were studied after 5 weeks and 17 weeks of hypercaloric diet com-pared to the control rats with not fat diet (Chow) or to rats not developing obesity (DIO-resistant DR). DIO rats of 7 weeks of age were exposed to specific diet ad libitum and after 5 weeks the ob-ese phenotype starts to develop. Food consumption, fat mass content, blood pressure, fasting insulin and glucose levels were moni-tored. The behavioral analysis included locomotor activity and anxiety-like behavior test, novel ob-ject recognition test, spatial learning, and memory test were performed. Magnetic resonance imaging (MRI) in the brain was performed to investigate possible gross anatomical changes. RT-PCR, immunochemical and immunohistochemical analysis were performed to evaluate neuronal and glial alterations. After long-term high fat diet exposure, body weight was remarkably increased in DIO rats com-pared to the control group and DR rats. Glycaemia was higher in DIO rats only after 17 weeks of the high fat diet. No differences in values of total cholesterol and triglycerides were observed. Sys-tolic blood pressure was higher in DIO rats only after 17 weeks of high-fat diet compared to age-matched Chow rats and DR rats. Furthermore increased oxidative stress was observed in the serum of DIO rats compared to Chow rats. The open-field test revealed, in the older DIO rats, a decrease of cumulative distance traveled, their number of rearings and increasing the total immobility time. Only older DIO rats showed a reduc-tion of retention latency time in the passive avoidance test. MRI did not show significant morpho-logical and vascular brain changes. Immunohistochemical and immunochemical analysis showed an increased expression of the glial-fibrillary acid protein in the frontal cortex and hippocampus of older DIO rats compared to age-matched Chow and DR rats. A decrease of neurofilament expression was found in the hippocampus of older DIO rats without decrease of the number of neurons. RT-qPCR analysis revealed a modula-tion in the Transient Receptor Potential (TRP) channels and synaptic components. These results indicate that obesity in rats, in addition to the development of correlate cerebrovascu-lar risk factors, causes brain injury characterized by astrogliosis, neurodegeneration and impaired learning and memory tasks. The identification of neurodegenerative changes in DIO rats may represent the first step to better characterize the neuronal modifications occurring in the obesity and propose pharmacological treatments or food strategies to counteract them. [1] WHO, World health Organisation, 2013. http://www.who.int/mediacentre/factsheets/fs311/en/ [2] R.B. Ervin, C.L. Ogden. Trends in intake of energy and macronutrients in children and adoles-cents from 1999–2000 through 2009–2010. NCHS Data Brief 2013, 113, 1 [3] R.M. Uranga, A.J. Bruce-Keller, C.D. Morrison, S.O. Fernandez-Kim, P.J. Ebenezer, et al.. In-tersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 2010, 114, 344 [4] H. Francis, R. Stevenson. The longer-term impacts of Western diet on human cognition and the brain. Appetite 2013, 63, 11