Age and High-Fat Diet Effects on Glutamine Synthetase Immunoreactivity in Liver and Hippocampus and Recognition Memory in Mice.

High-Fat Diet (HFD)-induced obesity may promote agerelated memory impairment via disturbances of ammonia-glutamine metabolism. We studied the effects of age and long-term HFD exposure on Glutamine Synthetase (GS) expression in the liver and hippocampus and recognition memory in mice. Adult (5-month-old) and aged (15-month-old) male C57BL/6 mice were exposed to control diet (CD, 14% calories from fat) or HFD (60% fat). Novel place recognition testing was conducted and tissue was collected after 4 and 5 months on HFD, respectively. Tissue GS expression levels were assessed using immunohistochemistry and image analysis. The obese mice developed moderate/severe hepatic steatosis. GS immunoreactivity was observed in perivenous hepatocytes and in hippocampal astrocytes and neuropil. Hepatic GS immunoreactivity density was higher in aged mice on HFD (n = 8) than CD (n = 13, P = 0.004). In aged mice, hippocampal GS immunoreactivity density was higher with HFD than CD (P = 0.037). In the novel place recognition test, aged mice were classified into impaired (n = 7) and unimpaired (n = 12), relative to adult mice (n = 22). Hippocampal GS immunoreactivity density was higher in impaired than unimpaired aged mice (P < 0.05). Long-term exposure of aged mice to HFD was associated with increased GS expression in the liver and hippocampus. Novel place recognition impairment in aged mice was associated with increased hippocampal GS expression. These findings suggest that excess ammonia is involved in the age-related effects of HFD exposure and in neurotoxicity.