Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism
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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31 P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1α in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an ≈60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1α expression on whole-body energy expenditure, and PGC-1α transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol- sn -3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKCθ, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.
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Muscle-specific transgenic overexpression of PPARα or PGC-1α, despite upregulating oxidative enzymes and enhancing fat oxidation capacity, makes mice more susceptible to diet-induced insulin resistance.
“However, despite impressive upregulation of several oxidative enzymes and markedly enhanced capacity for fat oxidation in muscle, both of these transgenic mouse models were more susceptible to diet-induced insulin resistance (Choi et al., 2008; Finck et al., 2005).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Choi et al., 2008
Both MCK-PPARα and MCK-PGC-1α transgenic mice have increased mitochondrial protein expression and enhanced fat oxidation capacity, yet are more susceptible to whole-body and skeletal muscle insulin resistance.
“Both of these transgenic mouse models had increased expression of multiple mitochondrial proteins, leading to enhanced capacity for fat oxidation, but contrary to the predicted outcome they were more susceptible to whole body and skeletal muscle insulin resistance.”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [19]
MCK-PGC1α mice fed a fat-enriched diet have increased intramuscular TAG, DAG, and lysophosphatidic acid.
“MCK-PGC1α mice had increased intramuscular levels of TAG, DAG and lysophosphatic acid when fed the fat-enriched diet [19].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [19]
The MCK-PGC1α transgene increases mitochondrial content in type II fibers 2.4-fold without affecting type I fibers.
“The MCK-PGC1α transgene caused a 2.4-fold increase in mitochondrial content of type II fibers without affecting type I fibers [19].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [19]
Transgenic PGC-1α overexpression in skeletal muscle did not improve the in vivo metabolic profile in mice.
“Contrary to predictions, however, transgenic PGC-1α overexpression in skeletal muscle did not improve the in vivo metabolic profile in mice (87).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [87]
Skeletal muscle of transgenic PGC-1α overexpressing mice had increased mitochondria but were more sensitive to high-fat-induced insulin resistance.
“Rather, although the skeletal muscle of these mice had increased mitochondria, they were also more sensitive to high-fat-induced insulin resistance.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [87]
Some mouse models that overexpress proteins promoting mitochondrial biogenesis display largely enhanced mitochondrial content in skeletal muscle but are insulin resistant.
“For instance, some of the mouse models that overexpress proteins promoting mitochondrial biogenesis display a largely enhanced mitochondrial content in skeletal muscle, but are insulin resistant (Finck et al, 2005; Choi et al, 2008).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Choi et al, 2008
High-level expression of PGC-1α can induce increases in lipid oxidation genes and parallel increases in expression of genes promoting lipid uptake and synthesis.
“Moreover, high-level expression of PGC-1␣ can induce not only increases in lipid oxidation genes but also parallel increases in expression of genes promoting lipid uptake and synthesis (270).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [270]
Insulin resistance in these mice was paralleled by accumulation of triglycerides and long-chain acyl CoA.
“Insulin resistance was paralleled by accumulation of triglycerides and long-chain acyl CoA (270).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [270]
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- Authors
- Choi, C. S., Befroy, D. E., Codella, R., Kim, S., Reznick, R. M., Hwang, Y.-J., Liu, Z.-X., Lee, H.-Y., Distefano, A., Samuel, V. T., Zhang, D., Cline, G. W., Handschin, C., Lin, J., Petersen, K. F., Spiegelman, B. M., & Shulman, G. I.
- Affiliations
- Gachon University (KR)
- Departments of aInternal Medicine and
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-16
- Volume
- 105
- Issue
- 50
- Pages
- 19926-19931
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2598730
- OpenAlex
- W2163394070
- Cited by
- 279
- References
- 47
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 11 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 21 · 2016: 22 · 2015: 19 · 2014: 19 · 2013: 29 · 2012: 22
- FWCI
- 15.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- edoc (University of Basel)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- National Institute on Aging (R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, U24DK76169, R01DK040936, U24DK059635, U24DK076169, P30DK040561, P30DK045735)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PGC-1α, skeletal muscle, mitochondrial biogenesis, insulin resistance, muscle glucose uptake, mitochondrial ATP production, fatty acid uptake, diacylglycerol, protein kinase C, IRS-1 tyrosine phosphorylation, type 2 diabetes, energy balance, transgenic mice
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Diet, Energy Metabolism, Fats, Fatty Acids, Glucose, Insulin, Insulin Resistance, Mice, Transgenic, Mitochondria, Muscle, Oxidation-Reduction, Transcription Factors, Trans-Activators, Gene Expression, Muscle, Skeletal, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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