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Obesogenic high fat western diet induces oxidative stress and apoptosis in rat heart

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Abstract

Feeding Wistar rats a high calorie “Western” diet (45% fat) for up to 48 weeks induces obesity and cardiac dysfunction, while a high fat diet (60% fat) induces obesity only. Here we investigated the molecular “footprints” of the two forms of diet-induced obesity in the heart. In rats fed Western diet for a long term, cardiac mRNA transcript levels of malic enzyme were decreased (−72%, P < 0.05), suggesting impaired anaplerotic flux of the Krebs cycle (KC) and mitochondrial dysfunction. In addition, there was a marked decrease in the expression of the transcription factor MEF2C (myocyte enhancer factor 2C) and its target gene SERCA2a (sarco-endo-plasmic reticulum Ca2+-ATPase). Oxidative stress was reflected in reduced transcript levels of manganese superoxide dismutase, glutathione peroxidase 1, and increased protein levels of mitochondrial transcription factor A, suggesting compensatory mitochondrial biogenesis in the face of increased mitochondrial damage. Oxidant injury was accompanied by increased protein glycosylation, increased transcript levels of glutamine fructose 6-phosphate amidotransferase 2, and decreased protein levels of acetyl Co-A carboxylase. Lastly, apoptosis was evident by TUNEL positivity and elevated mRNA transcript levels and activity of caspase 3. Consistent with these results, protein levels of Bcl2 were markedly reduced. We conclude that inadequate supplementation of KC intermediates due to reduced levels of malic enzyme, downregulation of MEF2C and its target gene SERCA2a, oxidative stress, and programmed cell death are all potential contributors to contractile dysfunction of the heart.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

αKGDH:

a-Ketoglutarate dehydrogenase

AMPK:

5′ AMP-activated protein kinase

ANOVA:

Analyses of variance

AT:

Acute term (1–7 days)

CPT:

Carnitine palmitoyl transferase

CTE:

Cytosolic thioesterase

GFAT:

Glutamine fructose 6-phosphate amidotransferase

GLUT:

Glucose transporter

GPAT:

Glycerol 3-phosphate acyltransferase

GPX1:

Glutathione peroxidase 1

HBSP:

Hexosamine biosynthetic pathway

HO-1:

Heme oxygenase 1

IT:

Intermediate term (16–24 weeks)

KC:

Krebs cycle

LT:

Long term (32–48 weeks)

ME:

Malic enzyme

MERF2c:

Myocyte enhancer factor 2c

MnSOD:

Manganese superoxide dismutase

MTE:

Mitochondrial thioesterase

mtTFA/TFAM:

Mitochondrial transcription factor A

NAD (H):

Nicotinamide adenine dinucleotide (reduced)

OXPAT:

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family in highly oxidative tissues

PC:

Pyruvate carboxylase

PCC:

Propionyl-CoA carboxylase

PARP:

Poly (ADP-ribose) polymerase

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

SERCA:

Sarco-endoplasmatic reticulum calcium ATPase

ST:

Short term (4–8 weeks)

TG:

Triglycerides

UCP:

Uncoupling protein

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Acknowledgments

This study was supported in part by a National Heart, Lung and Blood Institute grant (RO1HL73162). We thank Mei Gong for technical assistance, Tommy Reese for TUNEL staining, and Roxy A. Tate and Rebecca Salazar for help with the preparation of the manuscript.

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There are no financial conflicts.

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, The University of Texas Medical School at Houston, 6431 Fannin, MSB 1.246, Houston, TX, 77030, USA

    Kalpana Ballal, Christopher R. Wilson, Romain Harmancey & Heinrich Taegtmeyer

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  1. Kalpana Ballal
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  2. Christopher R. Wilson
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  3. Romain Harmancey
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  4. Heinrich Taegtmeyer
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Correspondence to Heinrich Taegtmeyer.

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Ballal, K., Wilson, C.R., Harmancey, R. et al. Obesogenic high fat western diet induces oxidative stress and apoptosis in rat heart. Mol Cell Biochem 344, 221–230 (2010). https://doi.org/10.1007/s11010-010-0546-y

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  • DOI: https://doi.org/10.1007/s11010-010-0546-y

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