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Effect of Dietary Fat and Sucrose Consumption on Cardiac Fibrosis in Mice and Rhesus Monkeys

Affiliations

Effect of Dietary Fat and Sucrose Consumption on Cardiac Fibrosis in Mice and Rhesus Monkeys

Niranjana Natarajan et al. JCI Insight.

Abstract

Calorie restriction (CR) improved health span in 2 longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared with NIA hearts. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed a UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared with mice fed the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.

Keywords: Aging; Cardiology; Cardiovascular disease; Fibrosis.

Conflict of interest statement

Conflict of interest: RTL is a cofounder and member of the scientific advisory board of, and holds private equity in, Elevian, a company that aims to develop medicines to restore regenerative capacity. Elevian provides sponsored research support to the Lee Laboratory.

Figures

Figure 1
Figure 1. In NHPs, cardiac fibrosis is more abundant in UW animals compared with those from NIA.
However, no significant difference in cardiac fibrosis was observed between control and CR samples in either cohort. (A) Representative Masson’s trichrome–stained NHP LV tissues from control and CR groups of the NIA and UW studies show greater extent of cardiac fibrosis in the UW cohort. Scale bar: 50 μm. (B) Cardiac fibrosis was not significantly affected by CR in the NIA and UW cohorts. P = n.s. (nonsignificant), and ***P < 0.001 by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U test. (C) Percentage of myocardial area occupied by fibrosis was evaluated by sex and dietary regimen. Fibrosis within each study was not significantly different between control and CR groups when matched by sex. There was greater fibrosis in UW control and CR, compared with NIA cohorts. **P < 0.01; ***P < 0.001, by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U test. (D) Total cardiac fibrosis was significantly greater in UW LVs compared with NIA. ***P < 0.001, Mann-Whitney U test. Scatter plots to represent the data are shown with median with interquartile range. n: NIA: total n = 42, (24 control [15 male, 9 female]; 18 CR [11 male, 7 female]); UW: total n = 49 (26 control [16 male, 10 female]; 23 CR [14 male, 9 female]). (E) Heatmap of normalized expression values of specific genes in NHP heart samples from NIA and UW studies as measured from NanoString experiments. Median normalized abundances of genes assayed are shown in rows, and the columns represent each of the 4 cohorts: NIA control, UW control, NIA CR, and UW CR. Significant differences and trends among the groups are indicated by yellow boxes around pairwise comparisons; *P < 0.05 pairwise 2-tailed t test with Benjamini-Hochberg FDR correction. n = 6 for all groups.
Figure 2
Figure 2. Mice fed the UW or the mNIA diet for 6 months have elevated body weights, higher fasting glucose levels, and increased cardiac fibrosis.
(A) Body weights of mice fed NIA diet for 6 months were significantly lower than chow, UW, and mNIA diet groups. **P < 0.01, by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U test. Scatter plots to represent the data are shown with median with interquartile range. (B) Heart weight to body weight ratios of mice in the 4 diet cohorts. *P < 0.05, by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney test. Scatter plots to represent the data are shown with median with interquartile range. (C) Representative Masson’s trichrome images of hearts from chow, NIA, UW, and mNIA diet groups (scale bar: 50 μm). Increased cardiac fibrosis observed in UW diet– and mNIA diet–fed mice was predominantly perivascular. (D) Percentage of fibrosis of UW and mNIA diet cohorts was significantly greater compared with chow and NIA diet cohorts. Overall P < 0.001, by Kruskal-Wallis test. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. P = n.s. (nonsignificant); *P < 0.05; **P < 0.01; ***P < 0.001. Scatter plots to represent the data are shown with median with interquartile range.
Figure 3
Figure 3. In mice, diet composition is associated with distinct transcriptional profiles.
(A) t-SNE visualization of global transcriptomic profiles (i.e., all expression levels of all transcripts) of hearts from mice fed chow, NIA, or UW diets. (B) PCA visualization of global transcriptomic profiles (i.e., all expression levels of all transcripts) of hearts from mice fed chow, NIA, UW, or mNIA diets. (C) Volcano plots illustrating transcripts that are differentially expressed between each pair of diets. (D) Bar graphs illustrating numbers of significantly differentially expressed transcripts between each pair of diets.
Figure 4
Figure 4. Summary of KEGG pathways in which significantly differentially expressed genes (mNIA vs. chow, mNIA vs. NIA, and NIA vs. mNIA) are overrepresented.
Figure 5
Figure 5. Pathway and protein network module analyses to identify key functional signatures that are upregulated in mNIA, compared with chow and NIA.
(A) Protein network modules involving significantly differentially expressed genes that have higher expression levels in mNIA compared with chow. (B) Protein network modules involving significantly differentially expressed genes that have higher expression levels in mNIA compared with NIA. (C) Protein network modules involving significantly differentially expressed genes that have higher expression levels in NIA compared with mNIA.

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