Cause of a high-fat diet

A high-fat diet has been shown as the major cause of obesity and insulin resistance. Surprisingly, considering the dramatic rise of insulin resistance throughout the developed nations and the growing interest in the role of insulin within the brain, there have been only a few studies examining the effects of this metabolic impairment in the central nervous system (CNS). Growing evidence has shown that insulin resistance, defined as a sharply diminished insulin receptor (IR) response to insulin within target tissues, has grown increasingly common in obese people.

The expression of insulin receptors (IRs) is found throughout the body, in organs or cells such as liver, muscle, fat, red blood cells and neurons in the CNS. In the CNS, insulin has been shown to regulate neurotransmitter release and synaptic plasticity, and the impairment of insulin signaling in the CNS has been shown to relate to neurodegenerative diseases. Evidence from clinical and animal studies suggests that insulin/IR signaling may play a role in learning and memory. Zhao and colleagues found that the up-regulation of IR in CA1 hippocampus is associated with short-term memory formation after a spatial learning experience. It has also been shown that insulin is required to produce memory improvement in elderly people and patients with Alzheimer's disease. Furthermore, clinical studies have shown that cognitive impairments are often found in association with increased insulin resistance.

The underlying mechanisms of IRs in learning and memory could involve the relationship between IRs and the synaptic plasticity in the CNS. Insulin has been shown to play a role in synaptic plasticity by acting on alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor trafficking. It has been demonstrated that insulin facilitates clathrin-dependent internalization of AMPA receptors, causing long-term depression (LTD) of AMPA receptor-mediated synaptic transmission in hippocampal CA1 neurons. This piece of evidence indicates that the neurofunctional IRs in the CA1 hippocampus is insulin-mediated LTD. Moreover, the activation of insulin turns on the protein kinase activity of the IR, which triggers cascades of signal transduction through its downstream substrate molecules. Several insulin receptor signaling pathways activated by IRs include insulin receptor substrate-1 (IRS-1). It has been demonstrated that rats trained in a spatial learning task showed the learning-specific increase in IRS-1 in the hippocampal synaptic membranes. These findings suggest that IR signaling plays a role in learning and memory by modulating activities of synaptic plasticity such as insulin-mediated LTD and by triggering signal transduction cascades such as IR, IRS-1 and Akt/PKB.

Diets have been shown to influence cognitive functions. In insulin resistance caused by fructose-fed hamsters, it has been shown that hippocampal synaptic plasticity, an important biological mechanism of learning and memory, was impaired. Excessive fat consumption has also been shown to play important and integral roles in the development of insulin resistance and type 2 diabetes. A recent study demonstrated that consumption of a high-calorie diet for 32 weeks reduced hippocampal synaptic plasticity and impaired cognitive function in rats. Furthermore, several studies suggest that consumption of a diet rich in fat for 3 months can develop peripheral insulin resistance and impede cognitive performance. These findings suggest that the development of insulin resistance can mediate the cognitive deficit associated with high-fat diet. However, the effect of high-fat diet on the neurofunctional IRs is still unclear. In addition, the effects of time-course of high-fat diet consumption on the neurofunctional IRs have never been investigated. Therefore, in this study we tested the hypothesis that high-fat diet consumption for a specific period of time can cause peripheral insulin resistance and can lead to impaired neuronal response to insulin (or neuronal insulin resistance). We used an electrophysiological study to investigate whether the neuronal responses to insulin (insulin-mediated LTD) are altered by high-fat diet consumption at different time course in order to detect the earliest stage of the disruption of the neurofunctional IRs. We also examined the alteration of biochemical activity of insulin receptor pathways: IRβ, IRS-1 and Akt/PKB, in the brain following each time course of high-fat diet consumption. Furthermore, we investigated whether the neuronal insulin resistance leads to neuronal ageing using the amount of nNOS-immunoreactive neurons as an indicator of neuronal ageing.