This hypothesis will be tested as described in the following specific aims:
Specific Aim 1: To determine whether rats with long-term high fat diet feeding have peripheral and neuronal insulin resistance, particularly in the hippocampal regions. We will use laboratory analysis for investigating peripheral insulin resistance (1.1) and the extracellular recording in acutely prepared brain slices to determine neuronal insulin resistance (1.2).
1.1 To investigate which time courses (2, 4, 8, 12, 20 weeks) of high fat-diet feeding can induce peripheral insulin resistance in a rat model.
1.2 To test whether the long-term high fat diets feeding induced peripheral insulin resistance can lead to neuronal insulin resistance in hippocampal regions. Measurement of the alteration in insulin-induced long term depression (LTD) in hippocampal slices will be performed and the comparison of LTD in hippocampus of between control and high fat-diet feeding rats will be made.
Specific Aim 2: To determine whether the neuronal insulin resistance following the long-term high-fat diet feeding occurs via changes in the function of the postsynaptic -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Our preliminary data shows that after 12 week high fat-diet feeding, rats had peripheral insulin resistance (Table 1) and the insulin response in hippocampal neurons decreased (Figure 3). We will use a combination of whole-cell voltage-clamp recordings and extracellular dendritic field potential recordings as well as pharmacological tools in acutely prepared brain slices to investigate the differences in postsynaptic activity of hippocampal neurons in high fat-diet fed groups and control groups.
Specific Aim 3: To investigate whether the long-term high-fat diet feeding induced peripheral insulin resistance can impair neuronal synaptic plasticity (long term potentiation (LTP) or LTD), in hippocampal circuits. We will use a combination of whole-cell voltage-clamp recordings and extracellular dendritic field potential recordings with different stimuli frequency in acutely prepared brain slices to investigate the differences in synaptic plasticity of hippocampal neurons in high fat-diet fed groups and control groups.
