High fat diet induces brain insulin resistance and cognitive impairment in mice

Abstract

High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice.

The Role of Interleukin-18, Oxidative Stress and Metabolic Syndrome in Alzheimer’s Disease

“…Mice fed a high fat diet develop obesity, lower glucose and insulin tolerance, and elicit insulin resistance in the brain, versus mice fed with a normal diet. The brains of these mice also exhibit biochemical changes associated with increased Aβ deposition and NFT formation, as well as decreased synaptic plasticity [101]. Sucrose-treated mice also show mitochondrial abnormalities, oxidative imbalance and a significant increase in Aβ levels as well as increases in phosphorylated tau (pTau) levels [102].…”

Studies of pathology and pharmacology of diabetic encephalopathy with KK‐Ay mouse model

“…This situation may cause a decrease of glucose utilization in astrocytes and subsequently reduce supports to neurons. Most of the energy and nutrition required by neurons obtained from astrocytes, and it was consistent with a change in the brain of AD, chronic hyperglycemia, and high‐fat dietary, which GLUT1 is also down‐regulated. But the mechanism of down‐regulation of GLUT1 remains to be studied.…”

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

“…reported no changes in the density of the glucose carriers GLUT1, widely expressed in the brain and the main glucose carrier at the BBB, and GLUT3, mainly located in neuronal membranes, in brain preparations obtained from db / db mice, when compared to wild‐type mice (Vannucci et al, ). In contrast, a recent study reported lower levels of both GLUT1 and GLUT3 in whole‐brain homogenates prepared from mice exposed to a diet rich in fat and sugar for 3 months, which develop an insulin‐resistant phenotype, relative to mice fed a regular chow (Kothari et al, ). Altogether, these observations lead us to speculate that reduced glucose transport and utilization is caused by changes in metabolic regulation according to cellular needs and adaptations to a diabetic and neurodegenerative state rather than reduced glucose carrier concentrations.…”

“…and GLUT3 in whole-brain homogenates prepared from mice exposed to a diet rich in fat and sugar for 3 months, which develop an insulin-resistant phenotype, relative to mice fed a regular chow (Kothari et al, 2017). Altogether, these observations lead us to speculate that reduced glucose transport and utilization is caused by changes in metabolic regulation according to cellular needs and adaptations to a diabetic and neurodegenerative state rather than reduced glucose carrier concentrations.…”