Abstract
Metabolic syndrome and diabetes impact brain function and metabolism. While it is well established that rodents exposed to diets rich in saturated fat develop brain dysfunction, contrasting results abound in the literature, likely as result of exposure to different high-fat diet (HFD) compositions and for varied periods of time. In the present study, we investigated alterations of hippocampal-dependent spatial memory by measuring Y-maze spontaneous alternation, metabolic profiles of the hippocampus, cortex and hypothalamus by 1H magnetic resonance spectroscopy (MRS), and levels of proteins specific to synaptic and glial compartments in mice exposed for 6 months to different amounts of fat (10, 45, or 60% of total energy intake). Increasing the dietary amount of fat from 10 to 45% or 60% resulted in obesity accompanied by increased leptin, fasting blood glucose and insulin, and reduced glucose tolerance. In comparison to controls (10%-fat), only mice fed the 60%-fat diet showed increased fed glycemia, as well as plasma corticosterone that has a major impact on brain function. HFD-induced metabolic profile modifications measured by 1H MRS were observed across the three brain areas in mice exposed to 60%- but not 45%-fat diet, while both HFD groups displayed impaired hippocampal-dependent memory. HFD also affected systems involved in neuro- or gliotransmission in the hippocampus. Namely, relative to controls, 60%-fat-fed mice showed reduced SNAP-25, PSD-95 and syntaxin-4 immunoreactivity, while 45%-fat-fed mice showed reduced gephyrin and syntaxin-4 immunoreactivity. For both HFD levels, reductions of the vesicular glutamate transporter vGlut1 and levels of the vesicular GABA transporter were observed in the hippocampus and hypothalamus, relative to controls. Immunoreactivity against GFAP and/or Iba-1 in the hypothalamus was higher in mice exposed to HFD than controls, suggesting occurrence of gliosis. We conclude that different levels of dietary fat result in distinct neurochemical alterations in the brain.
Highlights
The ever-increasing life expectancy has led to a dramatic increase in the prevalence of age-associated disorders namely metabolic syndrome and type 2 diabetes (T2D), and neurodegenerative disorders, such as Alzheimer’s disease (AD)
Fed glycemia was modified by high-fat diet (HFD) (F = 9.1, P = 0.001, Figure 1B), being significantly increased in 60%-fat fed mice compared to controls (+56 ± 14%, P < 0.001) and to 45%-fat fed mice (+45 ± 13%, P = 0.002)
After fasting for 6 h, mice showed a glycemia that was proportional to the amount of fat in the diet (F = 23.1; P < 0.001, Figure 1C), while insulinemia was increased in both HFD groups compared to controls (F = 9.2, P < 0.001, Figure 1D)
Summary
The ever-increasing life expectancy has led to a dramatic increase in the prevalence of age-associated disorders namely metabolic syndrome and type 2 diabetes (T2D), and neurodegenerative disorders, such as Alzheimer’s disease (AD). There is a growing body of epidemiological evidence suggesting that both metabolic syndrome and T2D increase the risk of developing age-related cognitive decline, mild cognitive impairment, vascular dementia, and AD (Frisardi et al, 2010; Duarte, 2015). Postmortem analyses of brains from dementia patients revealed that insulin receptors are downregulated, and pointed toward a major role of neuronal insulin resistance in the etiology of AD (Steculorum et al, 2014; Duarte, 2015). Insulin and insulin-like growth factor 1 (IGF-1), which have converging signaling pathways in the brain, regulate the neuronal control of energy and glucose homeostasis by acting on hypothalamic nuclei (Steculorum et al, 2014), and regulate cognitive processes through its actions on neurotransmission, synaptic plasticity, and neurogenesis within cortical and hippocampal circuits (Fernandez and TorresAlemán, 2012)
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