Abstract
Obesity arising from excessive dietary fat intake is a risk factor for cognitive decline, dementia and neurodegenerative diseases, including Alzheimer’s disease. Here, we studied the effect of long-term high-fat diet (HFD) (24 weeks) and return to normal diet (ND) on behavioral features, microglia and neurons in adult male C57BL/6J mice. Consequences of HFD-induced obesity and dietary changes on general health (coat appearance, presence of vibrissae), sensory and motor reflexes, learning and memory were assessed by applying a phenotypic assessment protocol, the Y maze and Morris Water Maze test. Neurons and microglia were histologically analyzed within the mediobasal hypothalamus, hippocampus and frontal motor cortex after long-term HFD and change of diet. Long periods of HFD caused general health issues (coat alterations, loss of vibrissae), but did not affect sensory and motor reflexes, emotional state, memory and learning. Long-term HFD increased the microglial response (increased Iba1 fluorescence intensity, percentage of Iba1-stained area and Iba1 gene expression) within the hypothalamus, but not in the cortex and hippocampus. In neither of these regions, neurodegeneration or intracellular lipid droplet accumulation was observed. The former alterations were reversible in mice whose diet was changed from HFD to ND. Taken together, long periods of excessive dietary fat alone do not cause learning deficits or spatial memory impairment, though HFD-induced obesity may have detrimental consequences for cognitive flexibility. Our data confirm the selective responsiveness of hypothalamic microglia to HFD.
Highlights
The consumption of a high-fat diet (HFD) and consequent obesity are associated with numerous disorders, including cardiovascular diseases, cancer, and metabolic disturbances such as in glucose metabolism and insulin resistance, as well as accumulation of adipose tissue [1–4]
Previous studies already reported about inflammatory microglial responses to variable durations of HFD in the hypothalamus, where microglia, the central nervous system (CNS) analogs of macrophages, and astrocytes are involved in body weight homeostasis and obesity [37, 45, 65, 66]
We found that long periods of HFD lead to microglial activation within the mediobasal hypothalamus
Summary
The consumption of a high-fat diet (HFD) and consequent obesity are associated with numerous disorders, including cardiovascular diseases, cancer, and metabolic disturbances such as in glucose metabolism and insulin resistance, as well as accumulation of adipose tissue [1–4]. Long-term diet-induced obesity does not lead to learning and memory impairment in mice. Several studies demonstrated that rodents with excessive dietary fat and sugar intake for months are impaired in hippocampal-dependent memory tasks [12–16]. Some feeding studies in adult rodents and humans indicated that even few days of obesity-induced diet is sufficient to affect the function of the hippocampus [10, 17– 21]. Yaseen et al (2019) and Khazen et al (2019) recently reported that acute exposure to HFD at juvenility in male rats is linked to impaired social recognition memory and compromised prefrontal plasticity, and it is associated with disrupted hippocampal-dependent memory and plasticity [16, 22]. Several studies indicated that adolescent HFD exerts more deleterious effects on hippocampal-dependent plasticity and memory as compared to HFD exposure during adulthood [23–25]. Numerous data indicate that HFD may activate signaling pathways with harmful effects in the hippocampus, and in the cortex [26–28]
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