Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats.

Non-alcoholic fatty liver disease (NAFLD) is a disorder observed in children and adults characterized by an accumulation of liver fat (>5% wet weight) in the absence of excessive alcohol intake. NAFLD affects 10 to 30% of the American population and is the most common cause of liver disease in the United States. NAFLD leads to serious disturbances in cardiovascular and hormonal function; however, possible effects on brain function have been overlooked. The aims of the present study were to test whether diet-induced NAFLD impairs hippocampal-dependent memory and to determine whether any observed deficits are associated with changes in hippocampal insulin signaling or concentrations of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). Post-weanling male Sprague-Dawley rats were fed a high fructose (60% of calories) or control diet for 12 weeks and then trained and tested in a spatial water maze. NAFLD was confirmed with postmortem measures of liver mass and liver lipid concentrations. NAFLD did not affect acquisition of the spatial water maze, but did impair retention tested 48 h later. Specifically, both groups demonstrated similar decreases in latency to swim to the escape platform over training trials, but on the memory test NAFLD rats took longer to reach the platform and made fewer visits to the platform location than control diet rats. There were no differences between the groups in terms of insulin-stimulated phosphorylation of insulin receptor β subunit (IR-β) and protein kinase B (PKB/AKT) in hippocampal slices or hippocampal BDNF or IGF-1 concentrations. Thus, these data indicate that NAFLD impairs hippocampal-dependent memory function and that the deficit does not appear attributable to alterations in hippocampal insulin signaling or hippocampal BDNF or IGF-1 concentrations.