PGC-1α gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle.
Open accessAbstract
There are multiple binding domains on the promoter region of the peroxisome proliferator activator receptor gamma coactivator-1 alpha (PGC-1alpha) gene, including a trio of insulin responsive elements that are activated by the forkhead box class-O (FoxO1) winged helix transcription factor, which is known to be regulated by acute transforming retrovirus thymoma (Akt). Here we show that in skeletal muscle biopsy specimens from healthy humans and cultured human skeletal myotubes, insulin phosphorylates Akt (Ser473) and FoxO1 (Thr24, Ser256), leading to reduced nuclear abundance of FoxO1 total protein. This is associated with an insulin-mediated repression of the mRNA expression PGC-1alpha and downstream genes associated with oxidative phosphorylation. In contrast, in muscle taken from insulin resistant humans or in palmitate-treated insulin resistant myotubes, neither Akt nor FoxO1 was phosphorylated by insulin, resulting in a failure for nuclear exclusion of FoxO1 total protein, and an inability for insulin to repress the mRNA expression of PGC-1alpha and down-stream genes. To determine whether the regulation of FoxO1 was Akt dependent, we next treated Akt2 -/- and wild-type mice with or without insulin. Insulin phosphorylated Akt and FoxO1 (Thr24, Ser256) resulting in a reduced nuclear expression of FoxO1 total protein in wild-type but not Akt2 -/- skeletal muscle. We conclude that insulin decreases the expression of genes involved in oxidative metabolism in healthy but not insulin resistant muscle, due to a decrease in FoxO1 phosphorylation and nuclear exclusion secondary to reduced Akt activity.
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PGC-1α expression may also be reduced as a consequence of promoter methylation or caused by insulin itself, obesity, and sustained lipid exposure.
“In turn, PGC-1␣ expression may also be reduced as a consequence of promoter methylation (146) or caused by insulin itself (145), obesity (126), and sustained lipid exposure (126).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [145]
Alterations in muscle PGC-1α and -β mRNA expression are observed in humans with insulin resistance-being reduced by nearly 50% in muscle from individuals with diabetes and in some populations of normoglycemic insulin-resistant humans.
“Moreover, alterations in muscle PGC-1␣ and - mRNA expression are observed in humans with insulin resistance-being reduced by nearly 50% in muscle from individuals with diabetes (122, 145) and in some populations of normoglycemic insulin-resistant humans (121, 124, 137).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [145]
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Nature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging
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- Authors
- Southgate, R. J., Bruce, C. R., Carey, A. L., Steinberg, G. R., Walder, K., Monks, R., Watt, M. J., Hawley, J. A., Birnbaum, M. J., & Febbraio, M. A.
- Affiliations
- RMIT University (AU)
- The University of Melbourne (AU)
- Deakin University (AU)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-10-03
- Volume
- 19
- Issue
- 14
- Pages
- 2072-2074
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2162645376
- Cited by
- 74
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 4 · 2020: 1 · 2018: 2 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 6
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- Open access
- green
- figshare.com
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Deakin Research Online (Deakin University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council
- Natural Sciences and Engineering Research Council of Canada
- Division of Arctic Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- PGC-1α, FOXO1, Akt phosphorylation, insulin signaling, skeletal muscle, insulin resistance, nuclear exclusion, oxidative phosphorylation, AKT2, transcriptional repression, palmitate, oxidative metabolism
- MeSH terms
- Forkhead Box Protein O1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Biopsy, Cell Nucleus, Cells, Cultured, Heat-Shock Proteins, Humans, Insulin, Insulin Resistance, Mice, Transgenic, Models, Biological, Oxygen, Phosphorylation, Promoter Regions, Genetic, RNA, Messenger, Serine, Threonine, Transcription Factors, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Enzymologic, Protein Structure, Tertiary, Muscle, Skeletal, Palmitic Acid, Proto-Oncogene Proteins c-akt, Mice, Forkhead Transcription Factors
About these checks
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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