Western diet augments metabolic and arterial dysfunction in a sex-specific manner in outbred, genetically diverse mice

Abstract

Western diet (WD), characterized by excess saturated fat and sugar intake, is a major contributor to obesity and metabolic and arterial dysfunction in humans. However, these phenotypes are not consistently observed in traditional inbred, genetically identical mice. Therefore, we sought to determine the effects of WD on visceral adiposity and metabolic/arterial function in UM-HET3 mice, an outbred, genetically diverse strain of mice. Male and female UM-HET3 mice underwent normal chow (NC) or WD for 12 weeks. Body mass and visceral adiposity were higher in WD compared to NC (P < 0.05). Female WD mice had greater visceral adiposity than male WD mice (P < 0.05). The results of glucose and insulin tolerance tests demonstrated that metabolic function was lower in WD compared to NC mice (P < 0.05). Metabolic dysfunction in WD as was driven by male mice, as metabolic function in female WD mice was unchanged (P > 0.05). Systolic blood pressure (BP) and aortic stiffness were increased in WD after 2 weeks compared to baseline and continued to increase through week 12 (P < 0.05). Systolic BP and aortic stiffness were higher from weeks 2-12 in WD compared to NC (P < 0.05). Aortic collagen content was higher in WD compared to NC (P < 0.05). Carotid artery endothelium-dependent dilation was lower in WD compared to NC (P < 0.05). These data suggest sex-related differences in visceral adiposity and metabolic dysfunction in response to WD. Despite this, arterial dysfunction was similar in male and female WD mice, indicating this model may provide unique translational insight into similar sex-related observations in humans that consume WD.

Keywords: aorta; arterial function; blood pressure; endothelium; fat; metabolic function; sugar.

FIGURE 1

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 2-way and 3-way mixed model ANOVA and 2-way ANOVA. Sidak post-hoc test was used to identify differences in body mass between groups (A) and sexes (B), as well as differences in Δ body mass (C), non-fasting blood glucose (D), non-fasting plasma insulin (E), and HOMA-IR (F) between groups/sexes. *P < 0.05 vs. NC. ^†P, 0.05 vs. NC within sex. ^‡P < 0.05 vs. male within group. Data are individual values and means ± SEM.

FIGURE 2

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 3-way and 4-way mixed model ANOVA. Sidak post-hoc test was used to identify differences in blood glucose in response to glucose tolerance test between groups (A) and sexes (B) at week 0, week 6 (C,D), and week 12 (E,F). *P < 0.05 vs. NC. ^†P < 0.05 vs. NC within sex. ^‡P < 0.05 vs. male within group. Data are means ± SEM.

FIGURE 3

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 3-way and 4-way mixed model ANOVA. Sidak post-hoc test was used to identify differences in blood glucose in response to insulin tolerance test between groups (A) and sexes (B) at week 0, week 6 (C,D), and week 12 (E,F). *P < 0.05 vs. NC. ^†P < 0.05 vs. NC within sex. ^‡P < 0.05 vs. male within group. Data are means ± SEM.

FIGURE 4

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 2-way and 3-way mixed model ANOVA. Sidak post-hoc test was used to identify differences in glucose tolerance test (GTT) area under the curve (AUC) between groups/sexes (A), as well as differences in insulin tolerance test (ITT) AUC between groups/sexes (B). *P < 0.05 vs. NC. ^†P < 0.05 vs. Week 0. ^‡P < 0.05 vs. Week 6. ^§P < 0.05 vs. NC within sex. ^#P < 0.05 vs. male within group. Data are individual values and means ± SEM.

FIGURE 5

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 2-way and 3-way mixed model ANOVA and 2-way ANOVA. Sidak post-hoc test was used to identify group differences in systolic blood pressure (BP) (A) and aortic pulse wave velocity (PWV) (B), sex-differences in systolic BP (C) and aortic PWV (D), as differences in Δ systolic BP (E) and Δ aortic PWV (F) between groups/sexes. *P < 0.05 vs. NC. 0, 2, 4, 6, 8, 10 P < 0.05 vs. the corresponding week, respectively. Data are individual values and means ± SEM.

FIGURE 6

Bivariate correlational analysis was used to determine the relationship between aortic pulse wave velocity (PWV) and systolic blood pressure (BP) (A), as well as the relationship between Δ in systolic BP and aortic PWV (B) in normal chow and Western diet-treated mice. Data are individual values.

FIGURE 7

Bivariate correlational analysis was used to determine the relationship between Δ in systolic blood pressure (BP) (A) or aortic pulse wave velocity (PWV) (B) with Δ in body mass in normal chow and Western diet-treated mice. Data are individual values.

FIGURE 8

Comparisons in normal chow (NC) and Western (WD) diet-treated mice. Data were analyzed using 3-way ANOVA. Sidak post-hoc test was used to identify groups/sex differences in aortic lumen diameter (A), medial cross-sectional area (CSA) (B), wall-to-lumen area (C), collagen (D), and elastin (E) content. Figures are accompanied by representative images of collagen and elastin staining. Black scale bars are equal to 500 μm. *P < 0.05 vs. NC. Data are individual values and means ± SEM.

FIGURE 9

Comparisons in normal chow (NC) and Western (WD) diet-treated male (M) and female (F) mice. Data were analyzed using 2-way and 3-way mixed model ANOVA. Sidak post-hoc test was used to identify differences in carotid artery vasodilation to acetylcholine in the presence and absence of L-NAME between groups (A) and sexes (B), as well as to identify differences in carotid artery vasodilation to sodium nitroprusside between groups (C) and sexes (D). *P < 0.05 vs. NC. Data are means ± SEM.

FIGURE 10

Bivariate correlational analysis was used to determine relations between maximal vasodilation to acetylcholine with systolic blood pressure (BP) (A) or aortic pulse wave velocity (PWV) (B), as well as relations between maximal vasodilation to sodium nitroprusside with systolic blood pressure (BP) (C) or aortic pulse wave velocity (PWV) (D) in normal chow and Western diet-treated mice. Data are individual values.