Abstract
BackgroundIn animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks. Brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA2 IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA2 VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured in brains subjected to high-energy microwave fixation.ResultsThe high-sucrose compared with control diet induced insulin resistance, and increased phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA concentration. Eicosanoid concentrations (prostaglandin E2, thromboxane B2 and leukotriene B4) did not change.ConclusionThese findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, but no changes in eicosanoids, in an animal model of the metabolic syndrome. These changes might contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome.
Highlights
In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment
In sucrose and control diet fed rats maintained for 8 weeks, we examined brain 1) expression of enzymes involved in arachidonic acid (AA) and docosahexaenoic acid (DHA) metabolism; 2) concentrations of prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and leukotriene B4 (LXB4); 3) mRNA levels of glialfibrillary acidic protein (GFAP) and tumor-necrosis factor-α (TNF-α), because of reported changes in these inflammatory markers in animal models of the metabolic syndrome [10]; 4) expression of brain-derived neurotrophic factor (BDNF), and of synaptophysin and drebrin as markers of synapto-dendritic injury [54]; and 5) esterified fatty acid concentrations in phospholipid subclasses, as well as unesterified fatty acids and lysophosphatidylcholine, as markers of phospholipid degradation
Because the 8-week high-sucrose feeding paradigm represents earlystage metabolic syndrome in the absence of pathological diabetes or obesity [50,51], these findings demonstrate changes in brain polyunsaturated fatty acids (PUFAs) metabolizing enzymes and composition in association with reduced BDNF and drebrin mRNA at an early disease stage
Summary
The metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Stimulation of AA signaling by glutamatergic, serotonergic, cholinergic or dopaminergic neuroreceptors, among others, triggers AA release by AA-selective Ca2+-dependent cytosolic phospholipase A2 (cPLA2 IVA) (reviewed in [19]). Disturbed brain AA and DHA metabolism has been linked to a number of neurodegenerative diseases, including Alzheimer’s disease and bipolar disorder [31,32,33], which are more common in individuals with the metabolic syndrome [4,5,6,7,8]
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