Cited by 1,265Cardiovascular Function and Risk FactorsCardiovascular Disease and AdiposityCardiac Fibrosis and Remodeling

Lipotoxic heart disease in obese rats: Implications for human obesity

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Zhou, Yan-Ting, Grayburn, Paul, Karim, Asad, Shimabukuro, Michio, Higa, Moritake, Baetens, Dany, Orci, Lelio, Unger, Roger H.·2000·Proceedings of the National Academy of Sciences

Abstract

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α. Levels of ceramide, a mediator of apoptosis, were 2–3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

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Crossref · 10.1073/pnas.97.4.1784

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  • A commonly described feature of most animal models of obesity is increased accumulation of intramyocellular triglycerides in the heart.

    “A commonly described feature of most animal models of obesity is increased accumulation of intramyocellular triglycerides in the heart. This has been reported in the hearts of genetic models such as ob/ob and db/db mice (29, 31, 34, 53), Zucker or fa/fa rats (394), and following high-fat feeding (346).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [394]

  • Accumulation of myocardial triglyceride and lipid metabolites such as ceramides is associated with cardiomyocyte apoptosis in Zucker rats, and reduced levels correlate with reduced apoptosis following thiazolidinedione treatment.

    “Accumulation of myocardial triglyceride and lipid metabolites such as ceramides has been associated with cardiomyocyte apoptosis in Zucker rats, and reduced levels correlate with reduced apoptosis following thiazolidinedione (TZD) treatment (394).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [394]

  • Increased interstitial fibrosis occurs in the hearts of Zucker (fa/fa) rats and UCP-DTA mice.

    “Increased interstitial fibrosis has been described in the hearts of Zucker (fa/fa) rats (350, 394) and in UCP-DTA mice (54).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [394]

  • In genetically obese Zucker fatty rats, LVH is present in young animals shortly after the development of diabetes, associated with increased LV function by echocardiography; they eventually develop significant LV dysfunction in vivo as evidenced by decreased fractional shortening, which can be reversed with TZD treatment.

    “In genetically obese Zucker fatty rats, LVH is present in young animals shortly after the development of diabetes. This is associated with increased LV function by echocardiography (104); however, they eventually develop significant LV dysfunction in vivo as evidenced by decreased fractional shortening. This can be reversed with TZD treatment (394).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [394]

  • Studies in Zucker fatty rats have shown increased apoptosis that was associated with increased cardiomyocyte levels of ceramide and triglycerides; treatment with a TZD reduced triglyceride and ceramide levels and reduced apoptosis.

    “Studies in Zucker fatty rats have shown increased apoptosis that was associated with increased cardiomyocyte levels of ceramide and triglycerides. Treatment of these mice with a TZD reduced triglyceride and ceramide levels and reduced apoptosis (394).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [394]

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  1. [18]Shimabukuro M, Zhou Y T, Levi M, Unger R H. Proc Natl Acad Sci USA. 1998;95:2498–2502. doi: 10.1073/pnas.95.5.2498. [[DOI](https://doi.org/10.1073/pnas.95.5.2498)] [[PMC free article](/articles/PMC19389/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9482914/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Proc%20Natl%20Acad%20Sci%20USA&author=M%20Shimabukuro&author=Y%20T%20Zhou&author=M%20Levi&author=R%20H%20Unger&volume=95&publication_year=1998&pages=2498-2502&pmid=9482914&doi=10.1073/pnas.95.5.2498&)] · DOI · Paper page
  2. [21]Bielawska A E, Shapiro J P, Jiang L, Melkonyan H S, Piot C, Wolfe C L, Tomei L D, Hannun Y A, Umansky S R. Am J Pathol. 1997;151:1257–1263. [[PMC free article](/articles/PMC1858093/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9358751/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Pathol&author=A%20E%20Bielawska&author=J%20P%20Shapiro&author=L%20Jiang&author=H%20S%20Melkonyan&author=C%20Piot&volume=151&publication_year=1997&pages=1257-1263&pmid=9358751&)]

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Authors
Zhou, Y.-T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., & Unger, R. H.
Affiliations
University of Geneva (CH)
Venue
Proceedings of the National Academy of Sciences
Published
2000-02-15
Volume
97
Issue
4
Pages
1784-1789
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2166788192
Cited by
1,265
References
21
Citations by year
2026: 10 · 2025: 21 · 2024: 23 · 2023: 34 · 2022: 28 · 2021: 42 · 2020: 31 · 2019: 38 · 2018: 45 · 2017: 50 · 2016: 48 · 2015: 50 · 2014: 53 · 2013: 50 · 2012: 78
FWCI
28.01
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK0270037, K08DK002700, R01DK002700)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
lipotoxic cardiomyopathy, obesity, Zucker diabetic fatty rats, ceramide, apoptosis, DNA laddering, inducible nitric oxide synthase, PPARα, fatty acid oxidation, troglitazone, cardiac dilatation, cardiac contractility, cardiac dysfunction
MeSH terms
Troglitazone, Age Factors, Animals, Blood Glucose, Body Weight, Chromans, Echocardiography, Heart Diseases, Humans, Insulin, Male, Microscopy, Electron, Myocardium, Obesity, Organ Size, Rats, Zucker, RNA, Messenger, Thiazoles, Apoptosis, Thiazolidinediones, Lipid Metabolism, Rats, DNA Fragmentation

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