The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index.
Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α: implications for metabolic disease
Abstract
Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordinated actions of broad transcriptional regulators such as the peroxisome proliferator activated receptors (PPARs) and PPARγ coactivator 1α (PGC1α). The application of transcriptomics and targeted metabolic profiling tools based on mass spectrometry has led to our finding that lipid-induced insulin resistance is a condition in which upregulation of PPAR-targeted genes and high rates of β-oxidation are not supported by a commensurate upregulation of tricarboxylic acid (TCA) cycle activity. In contrast, exercise training enhances mitochondrial performance, favoring tighter coupling between β-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high-fat diet. The exercise-activated transcriptional coactivator, PGC1α, plays a key role in coordinating metabolic flux through these 2 intersecting metabolic pathways, and its suppression by overfeeding may contribute to diet-induced mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from a mitochondrial disconnect between β-oxidation and TCA cycle activity. Understanding of this “disconnect” and its molecular basis may lead to new therapeutic approaches to combatting metabolic disease.
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“FAO intermediates may also create an unfavorable environment in the mitochondria, which contributes to the formation of ROS and the development of oxidative stress ([119](#B119), [120](#B120)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [120]
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“Accordingly, these coactivators are capable of regulating several distinct biological programs, including mitochondrial proliferation, b-oxidation, antioxidant defense, and lipogenesis (Lin et al. 2005).”
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- 10.1074/jbc.M507621200 · DOI · Paper page
- Muoio D.M., 2006, Annu. Rev. Biochem.
- Muoio D.M., 1999, Am. J. Physiol., 276, E913
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Skeletal muscle: A review of molecular structure and function, in health and disease
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Rector, R. S., Thyfault, J. P., Uptergrove, G. M., Morris, E. M., Naples, S. P., Borengasser, S. J., Mikus, C. R., Laye, M. J., Laughlin, M. H., Booth, F. W., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2009.11.030 · Cited by 488
Bruce, C. R., Hoy, A. J., Turner, N., Watt, M. J., Allen, T. L., Carpenter, K., Cooney, G. J., Febbraio, M. A., & Kraegen, E. W. (2009) · Diabetes · doi:10.2337/db08-1078 · Cited by 363
Metadata
- Authors
- Muoio, D. M., & Koves, T. R.
- Affiliations
- Duke University (US)
- Venue
- Applied Physiology, Nutrition, and Metabolism
- Publisher
- Canadian Science Publishing
- Published
- 2007-10
- Volume
- 32
- Issue
- 5
- Pages
- 874-883
- ISSN
- 1715-5312 (ISSN-L)
- 1715-5320
- OpenAlex
- W2134843156
- Cited by
- 129
- References
- 79
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 8 · 2015: 10 · 2014: 11 · 2013: 8 · 2012: 11
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Applied Physiology Nutrition and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG028930)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01-DK56112)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- skeletal muscle, fatty acid metabolism, peroxisome proliferator-activated receptors, PGC-1α, insulin resistance, fatty acid beta-oxidation, TCA cycle, mitochondrial dysfunction, exercise training, high-fat diet, obesity, type 2 diabetes, dyslipidemia, lipid overload, metabolic disorders
- MeSH terms
- Animals, Fatty Acids, Humans, Transcription Factors, Muscle, Skeletal, Peroxisome Proliferator-Activated Receptors
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