Neuroinflamação induzida por infusão intracerebroventricular de palmitato, tratada com Liraglutida (análogo do hormônio peptídeo similar ao glucagon 1): efeitos no hipotálamo e hipocampo

Abstract

The uncontrolled neuroinflammation is a key mechanism in the onset and progression of neurodegenerative diseases, and are related to insulin resistance. The glucagon-like peptide (GLP) -1 agonists, such as liraglutide, are well-known for their effects on glucose homeostasis and insulin sensitization they have been developed for use in the treatment of type 2 diabetes. Many evidences suggest that the GLP-1 analogues cross the blood brain barrier and acts as a neuroprotective agent. The liraglutide, despite its already known neuroprotective effects, has not yet been tested in a model of palmitate-induced neuroinflammation. Mice received intracerebroventricular infusion (ICV) of palmitate for 4 weeks and were treated for 2 weeks with liraglutide. We performed analyzes on body mass, carbohydrate metabolism, such as oral glucose tolerance test (TOTG) and intraperitoneal insulin tolerance test (TITI) and measurement of the insulin and GLP-1 plasmatic hormones. In the hypothalamus and adipose tissues, brown (BAT) and white, we evaluated by western blotting, RT-PCR and microscopy relating to neuroinflammation and metabolism (energy balance, thermogenesis, lipogenesis and lipolysis). In the hippocampus (CA1 and dentate gyrus regions) we evaluated markers related to neuroinflammation and, through confocal microscopy, we performed the morphological and molecular analysis of microglia and astrocytes. The ICV infusion of palmitate increased the body mass, decreased the glucose tolerance, and increased the insulin resistance. In the hypothalamus, palmitate increased the expression of the inflammatory markers: interleukin (IL)-1β, tumor necrosis factor (TNF)-α and altered the energetic balance, where we observed increased levels of neuropeptide Y (NPY) and decreased levels of pro-opiomelanocortin (POMC), in addition to hypothalamic insulin resistance. It was observed that palmitate increased the lipogenesis and the sectional area of white adipocytes and decreased the lipolysis. In BAT, palmitate increased the proteins related to fat accumulation and decreased thermogenesis. Liraglutide was effective in attenuating or reversing the hypothalamic effects associated with palmitate infusion, restoring energy control, attenuating neuroinflammation and insulin resistance, stimulating lipolysis and increasing thermogenesis in BAT. In the hippocampus, the ICV infusion of palmitate resulted in pronounced neuroinflammation, microgliosis and reactive astrogliosis. The microglia were present in higher density, had ameboid and hypertrophied morphology, and reduced the number of branches and junctions, besides expressing in more histocompatibility complex (MHC) -II. We observed in the hippocampus of the palmitate-infused groups an elevation in the levels of proinflammatory cytokines TNF-α and IL-6. The liraglutide induced the neuroprotective phenotype of the microglia, characterized by an increase in the complexity morphology of the microglia. This neuroprotective morphology was accompanied by a significant reduction in TNF-α and IL-6 expression. The study provides evidence that liraglutide may be a suitable treatment against the palmitate-induced neuroinflammation, which it is characterized by the impaired energy balance, intense expression of proinflammatory cytokines, reactive microgliosis and astrogliosis, which has been described as one of the primary causes of several pathologies of the central nervous system.