Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
Abstract
Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARgamma in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARgamma-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 microM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 microM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-d-glucose uptake and the oxidation of exogenous [(14)C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPARgamma to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPARgamma-mediated gene transcription.
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During resistance exercise, muscle contractions activate AMPK, which stimulates glucose uptake by promoting translocation of GLUT4 to cell surface.
“One key pathway involves the activation of AMPK. AMPK activation stimulates glucose uptake by promoting the translocation of glucose transporter GLUT4 to the cell surface, thereby enhancing the uptake of glucose into muscle cells (93).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [93]
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- Authors
- LeBrasseur, N. K., Kelly, M., Tsao, T.-S., Farmer, S. R., Saha, A. K., Ruderman, N. B., & Tomas, E.
- Affiliations
- Boston University (US)
- Whitehead Institute for Biomedical Research (US)
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2006-07
- Volume
- 291
- Issue
- 1
- Pages
- E175-E181
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2107333702
- Cited by
- 276
- References
- 50
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 12 · 2019: 10 · 2018: 12 · 2017: 7 · 2016: 11 · 2015: 15 · 2014: 18 · 2013: 16 · 2012: 21
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk019514-35)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK58825, DK-49147, T32DK007201, DK-19514, DK-007201-28, DK51586, R01DK049147)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- thiazolidinediones, AMPK, troglitazone, pioglitazone, skeletal muscle, cellular energy state, insulin sensitivity, type 2 diabetes, adiponectin, ACC phosphorylation, glucose uptake, fatty acid oxidation
- MeSH terms
- Troglitazone, Acetyl-CoA Carboxylase, Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Animals, Chromans, Enzyme Activation, Fatty Acids, Glucose, Hypoglycemic Agents, Male, Multienzyme Complexes, Oxidation-Reduction, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Muscle, Skeletal, Swiss 3T3 Cells, Thiazolidinediones, PPAR gamma, Mice, Rats, AMP-Activated Protein Kinases, In Vitro Techniques
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