Intermittent fasting protects against the deterioration of cognitivefunction energy metabolism and dyslipidemia in Alzheimer’s disease-induced estrogendeficient rats

摘要

Intermittent fasting may be an effective intervention to protect against age-related metabolic disturbances, although it is still controversial. Here, we investigated the effect of intermittent fasting on the deterioration of the metabolism and cognitive functions in rats with estrogen deficiency and its mechanism was also explored. Ovariectomized rats were infused with β-amyloid (25-35; Alzheimer’s disease) or β-amyloid (35-25, Non-Alzheimer’s disease; normal cognitive function) into the hippocampus. Each group was randomly divided into two sub-groups: one with intermittent fasting and the other fed ad libitum: Alzheimer’s disease-ad libitum, Alzheimer’s disease-intermittent fasting, Non-Alzheimer’s disease-ad libitum, and Non-Alzheimer’s disease-intermittent fasting. Rats in the intermittent fasting groups had a restriction of food consumption to a 3-h period every day. Each group included 10 rats and all rats fed a high-fat diet for four weeks. Interestingly, Alzheimer’s disease increased tail skin temperature more than Non-Alzheimer’s disease and intermittent fasting prevented the increase. Alzheimer’s disease reduced bone mineral density in the spine and femur compared to the Non-Alzheimer’s disease, whereas bone mineral density in the hip and leg was reduced by intermittent fasting. Fat mass only in the abdomen was decreased by intermittent fasting. Intermittent fasting decreased food intake without changing energy expenditure.Alzheimer’s disease increased glucose oxidation, whereas intermittent fasting elevated fatoxidation as a fuel source. Alzheimer’s disease and intermittent fasting deterioratedinsulin resistance in the fasting state but intermittent fasting decreased serum glucoselevels after oral glucose challenge by increasing insulin secretion. Alzheimer’s diseasedeteriorated short and spatial memory function compared to the Non-Alzheimer’s disease,whereas intermittent fasting prevented memory loss in comparison to ad libitum.Unexpectedly, cortisol levels were increased by Alzheimer’s disease but decreased byintermittent fasting. Intermittent fasting improved dyslipidemia and liver damage indexcompared to ad libitum. Alzheimer’s disease lowered low-density lipoprotein cholesteroland serum triglyceride levels compared to Non-Alzheimer’s disease. In conclusion,Alzheimer’s disease impaired not only cognitive function but also disturbed energy,glucose, lipid, and bone metabolism in ovariectomized rats. Intermittent fasting protectedagainst the deterioration of these metabolic parameters, but it exacerbated bone mineraldensity loss and insulin resistance at fasting in Alzheimer’s disease-inducedestrogen-deficient rats.Impact statementIntermittent fasting was evaluated for its effects on cognitive function and metabolicdisturbances in a rat model of menopause and Alzheimer’s disease. Intermittent fastingdecreased skin temperature and fat mass, and improved glucose tolerance with decreasingfood intake. Intermittent fasting also prevented memory loss: short-term and specialmemory loss. Therefore, intermittent fasting may prevent some of the metabolicpathologies associated with menopause and protect against age-related memorydecline.