Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses

Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte-specific ecto-nucleotide pyrophosphate phosphodiesterase over-expressing transgenic (AtENPP1-Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high-fat diet, AtENPP1-Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high-fat diet-fed AtENPP1-Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down-regulation of insulin receptor expression, and up-regulation of the free fatty acid receptor 1. We observed evidence of biochemical and functional changes in hippocampal synapses in mice in response to high-fat diet. Such effects were more pronounced in a transgenic animal model of adipocyte insulin resistance (AtENPP1-Tg) compared to their wild-type littermates. Animals exhibited alterations in synaptic lipid composition, decreased basal synaptic transmission at the Schaffer collaterals to CA1 synapses, decreased GluN1 receptor phosphorylation, decreased insulin receptor expression, and increased FFA1 receptor expression. We believe that our results provide a novel mechanistic link between obesity, adipose tissue dysfunction, and increased risk for cognitive impairment. CA, cornu ammonis; CA1, hippocampal cornu ammonis 1; DAG, diacylglycerol; FFA, free fatty acids; FFA1, free fatty acid receptor 1; GluN1, NMDA receptor 1 subunit; HFD, high-fat diet. We observed evidence of biochemical and functional changes in hippocampal synapses in mice in response to high-fat diet. Such effects were more pronounced in a transgenic animal model of adipocyte insulin resistance (AtENPP1-Tg) compared to their wild-type littermates. Animals exhibited alterations in synaptic lipid composition, decreased basal synaptic transmission at the Schaffer collaterals to CA1 synapses, decreased GluN1 receptor phosphorylation, decreased insulin receptor expression, and increased FFA1 receptor expression. We believe that our results provide a novel mechanistic link between obesity, adipose tissue dysfunction, and increased risk for cognitive impairment. CA, cornu ammonis; CA1, hippocampal cornu ammonis 1; DAG, diacylglycerol; FFA, free fatty acids; FFA1, free fatty acid receptor 1; GluN1, NMDA receptor 1 subunit; HFD, high-fat diet.