%0 Journal Article
%T The Role of Insulin and Insulin-Like Growth Factor-1/FoxO-Mediated Transcription for the Pathogenesis of Obesity-Associated Dementia
%A Lorna Moll
%A Markus Schubert
%J Current Gerontology and Geriatrics Research
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/384094
%X 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, ¦Â-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 ¡ú 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 ¡ú FoxO-mediated transcription for the pathogenesis of obesity-associated dementia. 1. Introduction 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]. Furthermore, midlife overweight and obesity might increase the risk for dementia during aging [2¨C4]. Hence, the role of obesity or overweight status in the development of cognitive decline or dementia is a major health concern and possibly associated with enormous health care costs. Prospective investigations on the role of BMI for the development of dementia did not provide a conclusive picture, yet. Some studies report no association or even decreased BMI to be associated with dementia or Alzheimer¡¯s disease [5, 6], and others suggested higher BMI to be a risk factor for dementia [7] or that overweight in middle age is associated with dementia decades later [8, 9]. It seems to be difficult to estimate the exact role of obesity itself for the initiation or progress of cognitive impairment. Furthermore, obesity is associated with a variety of cardiovascular risk factors influencing long-term cognitive performance.
%U http://www.hindawi.com/journals/cggr/2012/384094/