Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α: implications for metabolic disease

Muoio, Deborah M.; Koves, Timothy R.

doi:10.1139/h07-083

Cited by 129Peroxisome Proliferator-Activated ReceptorsAdipose Tissue and MetabolismMetabolism, Diabetes, and Cancer

Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α: implications for metabolic disease

Muoio, Deborah M., Koves, Timothy R.·2007·Applied Physiology, Nutrition, and Metabolism

DOI 10.1139/h07-083

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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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Fatty acid oxidation intermediates may also create an unfavorable environment in the mitochondria, which contributes to the formation of ROS and the development of oxidative stress.
“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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Impaired exercise-induced mitochondrial biogenesis in the obese Zucker rat, despite PGC-1α induction, is due to compromised mitochondrial translation elongation
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H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle
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Authors: Muoio, D. M., & Koves, T. R.
Affiliations: Duke University (US)
ORCID: Muoio, Deborah M.
Koves, Timothy R.
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
DOI: 10.1139/h07-083
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
Licence: www.nrcresearchpress.com/page/about/CorporateTextAndDataMining (tdm)
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 › 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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Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α: implications for metabolic disease

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