Hearts from Mice Fed a Non-Obesogenic High-Fat Diet Exhibit Changes in Their Oxidative State, Calcium and Mitochondria in Parallel with Increased Susceptibility to Reperfusion Injury

Littlejohns, Ben; Pasdois, Philippe; Duggan, Seána; Bond, Andrew; Heesom, Kate J; Jackson, Christopher L.; Angelini, Gianni; Halestrap, Andrew P.; Suleiman, M‐Saadeh

doi:10.1371/journal.pone.0100579

Cited by 56 publications

(58 citation statements)

References 80 publications

(103 reference statements)

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“…The proposed mechanism for increased I/R injury was a combination of elevated catalase level and inability to adapt to an increase in oxidative stress, fragmentation of mitochondria, reduced mitochondrial density and elevated diastolic [Ca 2+ ] i [1]. In this study we show for the first time that switching the diet from high-fat back to normal for a few weeks significantly reduces the vulnerability of isolated hearts to I/R.…”

Section: Discussionmentioning

confidence: 70%

Switching Back to Normal Diet Following High-Fat Diet Feeding Reduces Cardiac Vulnerability to Ischaemia and Reperfusion Injury

Littlejohns

Lin

Angelini

et al. 2014

Cell Physiol Biochem

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Background: We have recently shown that hearts of mice fed high-fat diet exhibit increased vulnerability to ischaemia and reperfusion (I/R) in parallel to changes in catalase protein expression, mitochondrial morphology and intracellular diastolic Ca²⁺. Aims: To determine whether switching from high-fat back to normal diet alters vulnerability to I/R and to investigate cardiac cellular remodelling in relation to the mechanism(s) underlying I/R injury. Methods and Results: Male C57BL/6J mice were fed a high-fat diet for 19-22 weeks; after which a subset of mice was switched back to normal diet for 4-6 weeks. Hearts from mice switched back to normal diet were more resistant to reperfusion injury compared to hearts from mice fed only high-fat diet. This was associated with a significant reversal in catalase expression (western blotting) and recovery of size and density of mitochondria (electron microscopy). In contrast, switching back to normal diet did not alter cardiomyocyte contractility or Ca²⁺ transients compared to high-fat diet. Conclusion: This study shows for the first time that switching the diet from high-fat back to normal reduces vulnerability to I/R. This effect is associated with changes in catalase levels and mitochondrial morphology without altering cardiomyocyte contractility or Ca²⁺ transients.

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Section: Discussionmentioning

confidence: 70%

Switching Back to Normal Diet Following High-Fat Diet Feeding Reduces Cardiac Vulnerability to Ischaemia and Reperfusion Injury

Littlejohns

Lin

Angelini

et al. 2014

Cell Physiol Biochem

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“…Several reports have demonstrated that HF45% diet increases the body weight gain (Huang et al, ; Turdi et al, ; Carrer et al, ; Zhang et al, ; Hua et al, ; Noyan‐Ashraf et al, ). However, another study showed that HF45% did not increase the body weight gain when compared to mice fed control diet (Littlejohns et al, ). Similarly, we found that HF45% diet was not able to increase the body weight in relation to LF diet‐fed mice.…”

Section: Discussionmentioning

confidence: 97%

MicroRNA Expression Signature Is Altered in the Cardiac Remodeling Induced by High Fat Diets

et al. 2015

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Recent studies have revealed the involvement of microRNAs (miRNAs) in the control of cardiac hypertrophy and myocardial function. In addition, several reports have demonstrated that high fat (HF) diet induces cardiac hypertrophy and remodeling. In the current study, we investigated the effect of diets containing different percentages of fat on the cardiac miRNA expression signature. To address this question, male C57Bl/6 mice were fed with a low fat (LF) diet or two HF diets, containing 45 kcal% fat (HF45%) and 60 kcal% fat (HF60%) for 10 and 20 weeks. HF60% diet promoted an increase on body weight, fasting glycemia, insulin, leptin, total cholesterol, triglycerides, and induced glucose intolerance. HF feeding promoted cardiac remodeling, as evidenced by increased cardiomyocyte transverse diameter and interstitial fibrosis. RNA sequencing analysis demonstrated that HF feeding induced distinct miRNA expression patterns in the heart. HF45% diet for 10 and 20 weeks changed the abundance of 64 and 26 miRNAs in the heart, respectively. On the other hand, HF60% diet for 10 and 20 weeks altered the abundance of 27 and 88 miRNAs in the heart, respectively. Bioinformatics analysis indicated that insulin signaling pathway was overrepresented in response to HF diet. An inverse correlation was observed between cardiac levels of GLUT4 and miRNA-29c. Similarly, we found an inverse correlation between expression of GSK3β and the expression of miRNA-21a-3p, miRNA-29c-3p, miRNA-144-3p, and miRNA-195a-3p. In addition, miRNA-1 overexpression prevented cardiomyocyte hypertrophy. Taken together, our results revealed differentially expressed miRNA signatures in the heart in response to different HF diets. J. Cell. Physiol. 231: 1771-1783, 2016. © 2015 Wiley Periodicals, Inc.

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“…We also observed mitochondrial genes to be up-regulated only in the livers of the mice in the reversal group. Mitochondrial dysfunction has been observed in obese and diabetic individuals and in HF diet-fed mice (45)(46)(47). The reversion of HFD to low fat diets in mice can result in reversion of some mitochondrial defects observed in heart cells (48).…”

Section: Discussionmentioning

confidence: 99%

Persistent Chromatin Modifications Induced by High Fat Diet*

Leung

Trac

et al. 2016

Journal of Biological Chemistry

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Obesity is a highly heritable complex disease that results from the interaction of multiple genetic and environmental factors. Formerly obese individuals are susceptible to metabolic disorders later in life, even after lifestyle changes are made to mitigate the obese state. This is reminiscent of the metabolic memory phenomenon originally observed for persistent complications in diabetic patients, despite subsequent glycemic control. Epigenetic modifications represent a potential mediator of this observed memory. We previously demonstrated that a high fat diet leads to changes in chromatin accessibility in the mouse liver. The regions of greatest chromatin changes in accessibility are largely strain-dependent, indicating a genetic component in diet-induced chromatin alterations. We have now examined the persistence of diet-induced chromatin accessibility changes upon diet reversal in two strains of mice. We find that a substantial fraction of loci that undergo chromatin accessibility changes with a high fat diet remains in the remodeled state after diet reversal in C57BL/6J mice. In contrast, the vast majority of dietinduced chromatin accessibility changes in A/J mice are transient. Our data also indicate that the persistent chromatin accessibility changes observed in C57BL/6J mice are associated with specific transcription factors and histone post-translational modifications. The persistent loci identified here are likely to be contributing to the overall phenotype and are attractive targets for therapeutic intervention.Obesity and related metabolic diseases result from both genetic and environmental factors, such as exercise and diet. However, the molecular mechanisms that contribute to disease progression remain unclear. Intriguingly, previously obese individuals have increased mortality compared with normal individuals, despite therapeutic intervention (1). This is reminiscent of "metabolic memory," a phenomenon originally described in diabetic patients in which micro-and macrovascular complications develop long after blood glucose is normalized (2-4). It has been hypothesized that epigenetic modifications, such as alterations to the chromatin and non-sequence changes to DNA, including DNA methylation, can contribute to this "metabolic memory" (5-7).It is now well established that epigenetic modifications can contribute to disease progression (8). One manner by which external environmental factors can influence molecular pathways is through alterations to chromatin. It has been shown that high fat (HF) 2 diet leads to chromatin accessibility changes in the liver tissue of mice (9). Intriguingly, the genomic loci with the greatest degree of diet-induced chromatin accessibility changes are largely strain-specific, indicating a role for genetics in this response (9). Previous studies examining diet-induced metabolic dysfunctions have shown that mice that transition from HF to diets that are low in fats do not completely revert to the same state as mice only maintained on low fat diets (10). The data indicate th...

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Hearts from Mice Fed a Non-Obesogenic High-Fat Diet Exhibit Changes in Their Oxidative State, Calcium and Mitochondria in Parallel with Increased Susceptibility to Reperfusion Injury

Cited by 56 publications

References 80 publications

Switching Back to Normal Diet Following High-Fat Diet Feeding Reduces Cardiac Vulnerability to Ischaemia and Reperfusion Injury

Switching Back to Normal Diet Following High-Fat Diet Feeding Reduces Cardiac Vulnerability to Ischaemia and Reperfusion Injury

MicroRNA Expression Signature Is Altered in the Cardiac Remodeling Induced by High Fat Diets

Persistent Chromatin Modifications Induced by High Fat Diet*

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