Abstract
Epidemiological studies suggest that being obese in midlife is a risk factor for cognitive decline and dementia in later life. Hyperinsulinemia is one of the most frequent endocrine features in overweight people which results in insulin desensitization. Thus, chronically high insulin levels have been identified as risk factor for dementia. Accordingly, chronically high insulin levels might be harmful for brain function. Furthermore, insulin and IGF-1-induced signaling is reduced in the brains of patients suffering from Alzheimer's disease (AD). Interestingly, studies in rodents suggest that reduced insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling decrease AD pathology, that is, β-amyloid toxicity. Data obtained in C. elegans indicate that the beneficial effect mediated via reduced IR/IGF-1R signaling might partially be induced via the forkhead-box O transcription factors (FoxO). In the mammalian brain, there are FoxO1, FoxO3a, and FoxO6 expressed. Surprisingly, high-fat diet specifically reduces the expression of FoxO3a and FoxO6 suggesting that IR/IGF-1 → FoxO-mediated transcription is involved in the pathogenesis of obesity-associated cognitive impairment. Therefore, the function of FoxO1 and FoxO3a has been investigated in animal models of Alzheimer's disease in detail. The current paper focuses on the role of IR/IGF-1 signaling and IR/IGF-1 → FoxO-mediated transcription for the pathogenesis of obesity-associated dementia.
Highlights
Obesity is characterized by a body mass index (BMI) of over 30 kg/m2
Data obtained in C. elegans indicate that the beneficial effect mediated via reduced insulin receptor (IR)/insulinlike growth factor-1 receptor (IGF-1R) signaling might partially be induced via the forkhead-box O transcription factors (FoxO)
High-fat diet reduces the expression of FoxO3a and FoxO6 suggesting that IR/insulin-like growth factors (IGFs)-1 → forkhead box O (FoxO)-mediated transcription is involved in the pathogenesis of obesity-associated cognitive impairment
Summary
Obesity is characterized by a body mass index (BMI) of over 30 kg/m2. The prevalence of obesity will rise to approximately 700 million people worldwide in 2015 [1]. Cognitive performance might influence the pathogenesis of obesity and being overweight the development of cognitive impairment, Current Gerontology and Geriatrics Research dementia, and neurodegeneration. This interrelationship between body weight and cognitive function implicates the need for lifetime studies and standardized tests to identify cause or consequences of obesity-associated dementia. Insulin and insulin-like growth factors (IGFs) have been suggested as important modifiers for the pathogenesis of neurodegenerative diseases, providing a link between obesity, type 2 diabetes (T2D), and cognitive impairment or even the pathogenesis of Alzheimer’s disease. The current review discusses the role of insulin and insulin-like growth factor-1/FoxO-mediated transcription for the pathogenesis of obesity-associated dementia from model organisms to humans
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