Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3
Open accessAbstract
LKB1 is a tumor suppressor that may also be fundamental to cell metabolism, since LKB1 phosphorylates and activates the energy sensing enzyme AMPK. We generated muscle-specific LKB1 knockout (MLKB1KO) mice, and surprisingly, found that a lack of LKB1 in skeletal muscle enhanced insulin sensitivity, as evidenced by decreased fasting glucose and insulin concentrations, improved glucose tolerance, increased muscle glucose uptake in vivo, and increased glucose utilization during a hyperinsulinemic-euglycemic clamp. MLKB1KO mice had increased insulin-stimulated Akt phosphorylation and a > 80% decrease in muscle expression of TRB3, a recently identified Akt inhibitor. Akt/TRB3 binding was present in skeletal muscle, and overexpression of TRB3 in C2C12 myoblasts significantly reduced Akt phosphorylation. These results demonstrate that skeletal muscle LKB1 is a negative regulator of insulin sensitivity and glucose homeostasis. LKB1-mediated TRB3 expression provides a novel link between LKB1 and Akt, critical kinases involved in both tumor genesis and cell metabolism.
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LKB1-MKO and AMPK α2 KO, β2 KO and α2 KD mice have lower starting glycogen levels in skeletal muscle.
“LKB1-MKO and AMPK α2 KO, β2 KO and α2 KD mice have lower starting glycogen levels in skeletal muscle [17,138-140], supporting a role for AMPK in glycogen synthesis.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [17]
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- Authors
- Koh, H.-J., Arnolds, D. E., Fujii, N., Tran, T. T., Rogers, M. J., Jessen, N., Li, Y., Liew, C. W., Ho, R. C., Hirshman, M. F., Kulkarni, R. N., Kahn, C. R., & Goodyear, L. J.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Goodyear, Laurie J.
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-11-01
- Volume
- 26
- Issue
- 22
- Pages
- 8217-8227
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1636784
- OpenAlex
- W2109340122
- Cited by
- 202
- References
- 54
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 11 · 2019: 5 · 2018: 12 · 2017: 11 · 2016: 14 · 2015: 10 · 2014: 15 · 2013: 15 · 2012: 10
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK36836, DK-68626, R01DK068626, P30DK036836, P30DK040561)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR45670, R01AR045670, F32AR04662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- LKB1, skeletal muscle, insulin sensitivity, glucose homeostasis, TRB3, Akt phosphorylation, AMPK, muscle glucose uptake, tumor suppressor, muscle-specific knockout, glucose tolerance
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Cell Line, Crosses, Genetic, Female, Glucose, Homeostasis, Insulin Resistance, Male, Multienzyme Complexes, Transcription Factors, Signal Transduction, Trans-Activators, Protein Serine-Threonine Kinases, Mice, Knockout, Muscle, Skeletal, Cell Cycle Proteins, PPAR alpha, Mice, AMP-Activated Protein Kinases
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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