Metformin reduces behavioral, but not metabolic, disturbances associated with high‐fat diet

Abstract Background APOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD), and obesity is a strong risk factor for developing dementia and cognitive disturbances. Metformin, the first line medication for Type II Diabetes, has been implicated in reducing metabolic and cognitive disturbances. Here we tested whether metformin ameliorated the disturbances associated with high fat diet (HFD) and whether metformin works equally on the APOE3 and APOE4 mice. Method Male and female human APOE3 and APOE4 knock‐in mice were fed either a HFD (45% kcal fat) or a low fat diet (LFD) (10% kcal fat) for 3 months (3 months‐6 months of age). During the last month of feeding, mice were given 300 mg/kg/day of metformin in drinking water. At the end of feeding, the following metabolic measurements were taken: weight, baseline glucose, and glucose tolerance. The mice were tested on the Open Field Test and Fear Conditioning apparatus. Result HFD induced a 30% increase in weight in male APOE3 mice and a 20% increase in male APOE4 mice. HFD also induced glucose intolerance in male APOE3 and APOE4 mice. Metformin did not reduce these metabolic disturbances. These metabolic disturbances were not seen in female mice on HFD. HFD decreased average speed and increased anxiety‐like behavior in APOE4 females on the open field test; metformin reduced these effects. With fear conditioning, there was a decrease in context based freezing behavior in female APOE3 mice on HFD, again with a metformin‐associated recovery. There were no behavioral effects of HFD on male mice. Conclusion HFD induced metabolic disturbances in male mice, but there were no differences between APOE genotypes and metformin did not reduce these metabolic disturbances. Furthermore, behavioral effects were only seen in female mice with metformin assisting in the rescue of these effects. The next step is to examine the alterations in the CNS due to HFD and metformin.