Sex-Specific Effects of High Fat Diet on Indices of Metabolic Syndrome in 3xTg-AD Mice: Implications for Alzheimer's Disease

Abstract

Multiple factors of metabolic syndrome have been implicated in the pathogenesis of Alzheimer's disease (AD), including abdominal obesity, insulin resistance, endocrine dysfunction and dyslipidemia. High fat diet, a common experimental model of obesity and metabolic syndrome, has been shown to accelerate cognitive decline and AD-related neuropathology in animal models. However, sex interacts with the metabolic outcomes of high fat diet and, therefore, may alter neuropathological consequences of dietary manipulations. This study examines the effects of sex and high fat diet on metabolic and AD-related neuropathological outcomes in 3xTg-AD mice. Three month-old male and female 3xTg-AD mice were fed either standard or high fat diets for 4 months. Obesity was observed in all high fat fed mice; however, ectopic fat accumulation, hyperglycemia and hyperinsulinemia were observed only in males. Interestingly, despite the different metabolic outcomes of high fat diet, the neuropathological consequences were similar: both male and female mice maintained under high fat diet exhibited significant worsening in behavioral performance and hippocampal accumulation of β-amyloid protein. Because high fat diet resulted in obesity and increased AD-like pathology in both sexes, these data support a role of obesity-related factors in promoting AD pathogenesis.

Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice

“…Here we observed that HFD significantly exacerbated Aβ burden and behavioral impairment when introduced in early life, prior to significant preexisting pathology. This finding is consistent with our previous observation that four-month exposure to HFD introduced at age 3 mo significantly increased Aβ load and worsened performance in the spontaneous alternation task in male and female 3xTg-AD mice [38]. Similar findings of worsened AD-related pathology by early exposure to high-fat and/or high sugar diets have been reported in other AD transgenic strains, including Tg2576 [54], APP Swe/Ind [55], and APP/PS1 [56].…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…This relationship may be especially important for women, as women are both more at risk for AD (Li and Singh, 2014), and experience an increase in central adiposity at menopause (Meyer et al, 2011; Sugiyama and Agellon, 2012). While there exists some evidence of sex differences in obesity-associated AD risk (Barron et al, 2013; Hwang et al, 2010; Wolf et al, 2012), results are inconclusive and more work is needed to determine the nature of this relationship. Two factors that may be mechanistically important in the relationship between obesity and AD are apoE4 and inflammation.…”

“…A commonly used approach is the use of high fat diet (HFD) in rodents, which yields diet-induced obesity (DIO). Using this model, our lab and others have shown that DIO in transgenic mouse models of AD increases levels of Aβ (Barron et al, 2013; L. Ho et al, 2004; Julien et al, 2010; Kohjima et al, 2010), a key protein in the initiation and progression of AD (Selkoe, 2011).…”

“…These studies suggest that adverse metabolic outcomes can be exaggerated in the presence of AD, but genetically induced metabolic outcomes do not necessarily increase AD pathology. Interestingly, complementary findings in an AD transgenic mouse with DIO also suggest that metabolic disturbance may not be the driving force in promotion of AD pathogenesis (Barron et al, 2013). In summary, a number of studies in animal models have demonstrated increased AD-like pathology in the presence of diet- and pharmacologically-induced as well as genetically-induced obesity and metabolic disturbances.…”

“…Our own lab has demonstrated that although both male and female AD transgenic mice become obese on HFD, only males exhibit significant ectopic fat accumulation, hyperglycemia, and hyperinsulinemia (Barron et al, 2013). Despite differential effects of HFD on metabolic outcomes, both males and females have increased Aβ deposition (Barron et al, 2013), suggesting that AD-related pathology is accelerated by other obesity-induced effects, perhaps including inflammation.…”