About this Research Topic
Metabolic syndrome and obesity involve dysregulation of adipokines (leptin, adiponectin) and hyperglycemia caused by the gradual development of insulin resistance and type 2 diabetes. Recently, progranulin has also been described as an adipokine involved in insulin signaling. Adipokines are particularly regulated by the intake of fat, and different types of fat have an impact on lipid rafts, which regulate multiple cellular functions. Metabolic syndrome also involves low-grade inflammation, oxidative and nitrosative stress, which also have effects on levels of adipokines, as well as lipid rafts, inflammasome activation and production of inflammatory mediators, including interleukin 1-beta and -18. Globular adiponectin resembling tumor necrosis factor-alpha (TNF-alpha, cachexin) also belongs to inflammatory mediators in metabolic syndrome.
Dysregulated adipokines, hyperglycemia, oxidative, and nitrosative, as well as inflammatory mediators, are all risk factors for neurodegenerative diseases, such as Alzheimer’s disease (AD) and Multiple Sclerosis. Adipokines, their receptors, and interactions with other regulatory proteins, could also be neuroprotective since some of them exhibit anti-inflammatory properties. For instance, progranulin interacts with prosaposin, a secreted protein with neurotrophic and neuroprotective functions. On the other hand, adipokines may also have a role in aggregation and degradation of proteins involved in neurodegenerative diseases.
Brain tissue, which contains around 60% fat and particularly a high content of omega-3 polyunsaturated fatty acid in neuronal and glial membranes, is highly vulnerable to oxidative damage. Further, excess intake of dietary fat seems to lead to the increased lipid content of brain tissue, with likely substantial consequences also for brain function by multiple mechanisms. Metabolic syndrome also influences the brain vascular system depending on the nutrient status. Damages in the brain vasculature can cause microhemorrhages with the release of oxidative stress-involved iron, blockades, and leakages of the blood-brain barrier. Brain vascular damages increase the risk of neurodegeneration in multiple ways, including hypoxia, reperfusion injury involving neuroinflammation, and oxidative stress. In addition, oxidative stress also increases during aging, causing insulin resistance, and increased secretion of leptin, IL-6, and TNF-alpha by adipocytes, but decreased secretion of adiponectin. Further, lipid accumulation in aged microglia has recently been shown to increase the release of oxidative products, which can also activate inflammasomes.
Oxidant release has an impact on surrounding cells, their membranes, and lipid rafts. Lipid rafts, which are cholesterol-rich microdomains in cellular membranes marked by the presence of caveolin and flotillin, are associated with various signaling pathways, cell adhesion, membrane trafficking, and axonal growth. Proteins involved in AD pathogenesis, including amyloid precursor protein and its processing enzymes BACE-1 and gamma-secretase, are enriched in lipid rafts, a localization that is thought to play roles in modulation of APP processing to amyloid-beta. Lipid rafts also play a role in alpha-synuclein aggregation, a protein involved in Parkinson’s disease and seems to be involved in the regulation of metabolism. Lipid rafts likely have yet poorly understood impacts also on autoimmune diseases, including Multiple Sclerosis.
Thus, metabolic syndrome and obesity can change the expression of numerous factors that impact neuronal functions, although the changes may also depend on the nutrients that the long-lasting high energy diet has contained or lacked. The aim of this Research Topic is to further our understanding of the mechanisms underlying the pathogenesis of neurodegenerative diseases by bridging metabolic syndrome as a risk factor and the onset of neurodegeneration. We encourage authors to highlight the factors and changes related to metabolic syndrome and obesity, which play roles in multiple neurodegenerative diseases. This project may also generate new ideas for neurodegenerative diseases and the pathways of their development.
Keywords: Adipokines, Lipid rafts, Oxidative stress, Inflammatory proteins
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