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.

Figure 1. Obesity and adiposity in male and female high fat fed 3xTg-AD mice.

A, Body weight in male and female 3xTg-AD mice across the 4 month feeding period. B, Percent change in body weight relative to baseline weight after 4 months of feeding with either standard or high fat diet. C, Abdominal retroperitoneal fat pad weight in male (solid bars) and female (open bars) 3xTg-AD mice. D, Representative images of hematoxylin-stained livers in male and female mice fed regular and high fat diets. E, Quantification of microvesicular (<15 µm) and macrovesicular (>15 µm) fat accumulation in liver. F. Serum testosterone and estradiol levels in male and female mice respectively. Data presented as mean ± SEM.† p<0.001 relative to matched time point males fed regular diet. ‡p<0.001 relative to matched time point females with regular diet. **p<0.001 relative to regular diet fed mice. *p<0.01 male versus female mice. γp<0.05 relative to sex-matched regular diet fed mice.

Figure 2. Elevated fasting blood glucose and insulin levels in high fat fed male but not female 3xTg-AD mice.

A, Fasting blood glucose concentrations in male and female 3xTg-AD mice across the 4 month feeding period. B, Fasting insulin concentrations in male (solid bars) and female (open bars) 3xTg-AD mice after 4 months of feeding with either standard or high fat diet. C, Insulin resistance index, HOMA-IR. Data presented as mean ± SEM. *p<0.001 relative to standard diet group at the matched sex and time point; † p<0.001 relative to matched sex standard diet group.

Figure 3. Ovarian hormones protect high fat fed female mice against hyperglycemia.

A, Body weight in female 3xTg-AD mice was not affected by ovariectomy (OVX) in either standard or high fat groups. B, High fat diet increased abdominal retroperitoneal fat pad weight in sham-operated (solid bars) and ovariectomised (open bars) female 3xTg-AD mice equally. C, High fat diet increased fasting glucose concentrations in high fat fed female 3xTg-AD mice following ovariectomy D, Fasting insulin concentrations in sham-operated (solid bars) and ovariectomised (open bars) female 3xTg-AD mice after 4 months of feeding with either standard or high fat diet. C, Insulin resistance index, HOMA-IR. Data presented as mean ± SEM. *p<0.001 relative to regular diet fed mice; † p<0.001 relative to all other groups.

Figure 4. Impaired behavioral deficits in high fat fed 3xTg-AD mice.

A, Spontaneous alternation behavior (SAB) in the Y-maze in standard and high fat fed male and female 3xTg-AD mice. B, Object recognition performance in standard and high fat fed female 3xTg-AD mice at 2 and 18 hrs after training (2 and 18 hr probe). *p<0.001 relative to matched sex with standard diet. Data presented as mean ± SEM. *p<0.001 relative to matched sex with standard diet. † p<0.001 relative to matched probe trial.

Figure 5. High fat diet increases Aβ accumulation in the hippocampus of male and female 3xTg-AD mice.

A, Hippocampus CA1 Aβ immunoreactivity load values. B–E, Representative photomicrographs show Aβ immunoreactivity in the hippocampus CA1 regions in standard diet fed male (B) and female (C) 3xTg-AD mice, and high fat fed male (D) and female (E) 3xTg-AD mice. F, Subiculum Aβ immunoreactivity load values. G–J, Representative photomicrographs show Aβ immunoreactivity in the subiculum regions in standard diet fed male (G) and female (H) 3xTg-AD mice, and high fat fed male (I) and female (J) 3xTg-AD mice. Data presented as means ± SEM. *p<0.05 compared to all other groups. *p<0.001 relative to matched sex with standard diet.