GLIOSIS RELATED TO METABOLIC SYNDROME: EVIDENCES IN OBESE ZUCKER RAT BRAIN

Metabolic syndrome (MetS) is characterized by obesity, insulin resistance, dyslipidemia, and hyper-tension. Obesity is a relevant medical challenge being associated with the development of chronic diseases affecting also nervous system. Obesity and MetS, increases the risk of atherosclerotic vas-cular disease, type-2 diabetes mellitus (T2DM) and all-cause mortality [1]. Large clinical studies have considered MetS and its individual components a cause of increased ce-rebrovascular disease. Induction of neuroinflammation, increased production of free radicals, altera-tions in neurotrophic factors and reduction of insulin transport into the brain have been reported in patients with MetS [2]. The obese Zucker rats (OZRs), with a mutation in leptin receptors, represent a model of type II di-abetes mellitus, characterized by the simultaneous occurrence of obesity, hyperglycemia, hyperinsu-linemia, hyperlipidemia and moderate hypertension similar to MetS [3, 4]. This study has investigated brain microanatomy of OZRs compared with their non-obese cohort lean Zucker rats (LZRs) to assess possible relationships between MetS, glial activation, and brain injury. Male OZRs and LZRs of 12, 16 and 20 weeks of age were used. Body weight, blood pressure, and blood chemistry parameters were checked every two weeks and before killing. Behavioral tests (open-field and passive-avoidance) were performed to identify possible cognitive changes. The brain was processed for immunochemical and immunohistochemical analysis of glial-fibrillary acid protein (GFAP) immunoreactive astrocytes and for the expression of IBA-1 as a marker of microglial activation. OZRs of different ages, showed higher body weight, systolic pressure, glycemia and insulin resis-tance, higher triglycerides and cholesterol levels in comparison with LZRs. An age-dependent in-crease of these parameters was found in OZRs. An increase of oxidative stress in plasma and in the brain of OZRs was found. In hippocampus immunoblots analysis for GFAP revealed that the intensity of its band increased in OZRs rats compared to LZRs rats, in particular in the 20-weeks-old OZRs. Morphological and immunochemical analysis revealed an increase of GFAP im-munoreactive astrocytes compared to LZRs. In the hippocampus hyper-reactive astrocytes were observed in the molecular layer of CA1 subfield where the size of astrocytes was higher compared to LZRs at the different age. Similar findings were found in the hippocampus. In this area, an increased size of GFAP immunoreactive astrocytes in different sub-fields and dentate gyrus of OZRs was found compared to LZRs. Opti-cal and confocal laser microscopy identified in the brain of 20-weeks-old OZRs an increase in the number of hyperramified microglia elements characterized by increased branching of processes as well as lengthening of processes. Microglial elements characterized by swollen, truncated processes, and enlarged cell bodies were found particularly in the hippocampus. The open-field test revealed the OZRs in all parameters a decrease of cumulative distance traveled, their number of rearings and increasing the total immobility time. Only in 20 week-old SHR a sig-nificant decrease of the ratio between time in zone 1 and the central zone was ob-served. This indi-cates a condition of anxiety not mediated by an increase of immobility time. OZRs showed a reduc-tion of retention latency time in the emotional learning task. The present study has shown that GFAP-immunoreactive astrocytes and microglia activation in-crease in the brain of OZRs, pointing out a suffering of nervous tissue in a condition of hypergly-cemia and hypertension, and/or a tendency of astrocytes to protect neuronal microenvironment. These observations consistent with previous studies, confirm that reactive gliosis is associated with metabolic complications in OZRs. In terms of practical consequences, these data may help to better manage MetS progression and the correlations with neurodegenerative processes. [1] Samson SL, Garber AJ. Metabolic syndrome. Endocrinol Metab Clin North Am. 2014;43:1-23. [2] Ricci G, Pirillo I, Tomassoni D, Sirignano A, Grappasonni I. Metabolic syndrome, hypertension, and nervous system injury: Epidemiological correlates. Clin Exp Hypertens. 2017;39:8-16. [3] Fellmann L, Nascimento AR, Tibiriça E, Bousquet P.Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther. 2013;137:331-40. [4] Tomassoni D, Nwankwo IE, Gabrielli MG, Bhatt S, Muhammad AB, Lokhandwala MF, Taye-bati SK, Amenta F. Astrogliosis in the brain of obese Zucker rat: a model of metabolic syndrome. Neurosci Lett. 2013;543:136-41.