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

Abstract

Metabolic syndrome (MetS) is an association between obesity, dyslipidemia, hyperglycemia, hypertension, and insulin resistance. A relationship between MetS and vascular dementia was hypothesized. The purpose of this work is to investigate brain microanatomy alterations in obese Zucker rats (OZRs), as a model of MetS, compared to their counterparts lean Zucker rats (LZRs). 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. Body weight 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 was observed. The BBB of older OZRs revealed an increased expression of AQP4 likely related to the development of edema. A down-regulation of GLUT1 was found in OZRs of 12 weeks of age, whereas it increased in older OZRs. The behavioral 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 metabolic alterations induce neurodegeneration.

Altered Brain Cholinergic and Synaptic Markers in Obese Zucker Rats

“…As well as in the DIO model, we have previously reported in OZRs blood-brain barrier (BBB) alterations, neuronal loss, and gliosis both in the frontal cortex and in the hippocampus [13]. The behavioral tests revealed cognitive alterations in older OZRs as well as in DIO rats [12,14].…”

“…Although there are numerous data regarding the metabolic alterations in obese conditions and the development of neuroinflammation [8,9,12,14,31], no mechanism has been presented concerning obesity-related cholinergic and synaptic impairments in the brain. Therefore, this study was designed to investigate whether the memory and learning impairments in older OZRs [14] were also related to cerebral cholinergic and synaptic alterations, specifically identifying the markers that were implicated. The investigation was carried out in brain areas, in which cholinergic neurotransmission is widely represented: the frontal cortex, especially the motor region, and the hippocampus, which is involved in learning and memory tasks [14].…”

Underlying Susceptibility to Eating Disorders and Drug Abuse: Genetic and Pharmacological Aspects of Dopamine D4 Receptors

“…In fact, the PFC has anatomical connections with feeding-related areas, including the lateral hypothalamus, NAc shell and limbic reward sites [ 153 , 154 ]. The PFC circuitry is linked with cognitive aspects of searching for food [ 155 ], self-control, salience attribution and awareness [ 156 ], reward-based decision-making [ 66 ], and a dysregulation of such circuit might lead to the development of obesity [ 157 , 158 , 159 , 160 ]. In keeping with this latter observation, different imaging studies suggested the PFC activation in response to food-related cues [ 161 , 162 , 163 ]; such activation is also implicated in yohimbine-induced reinstatement of food seeking in rodents [ 164 , 165 ].…”

Lycopene Supresses Palmitic acid-induced Neuro-oxidoinflammation via Attenuation of Oxidative stress and NF-κB-p65 activation in Female Rats

“…The hyperproliferation and in ltration of these pro-in ammatory mediators and high metabolic demand of the brain predisposes it to oxidative stress, which exacerbates the neuroin ammation (Camandola and Mattson, 2017). Oxidative stress-induced neuroin ammation alters neurotrophic factors levels, disrupts neurotransmission balance, and contributes to neuronal damage and cognitive de cit (Tangvarasittichai, 2015;Chen et al, 2019;Tomassoni et al, 2020). Moreover, dysregulation of lipids, such as triacylglycerol and cholesterol correlates positively with neurodegenerative diseases (Chen et al, 2019).…”

“…Lycopene Supresses Palmitic acid-induced Neurooxidoin ammation via Attenuation of Oxidative stress and NF-κB-p65 activation in Female Rats Introduction Neuro-in ammation (arising from meta-in ammation) describes an immuno-metabolic disorder of the nervous system, arising from derangements of the metabolic and in ammatory pathways in response to various cues including infection, autoimmunity, nutrients, or toxic metabolites (Tomassoni et al, 2020). Nutrients (such as free fatty acids) may accumulate in the nervous tissue such as the microglia due to excessive positive energy balance.…”