Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels
Open accessAbstract
Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and β-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.
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Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways, increasing lipolysis and beta-oxidation in white adipose tissue and reducing neoglucogenesis.
“Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways [100], increasing lipolysis and ß-oxidation in white adipose tissue [102] and reducing neoglucogenesis [2].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [102]
Metformin can upregulate uncoupled proteins 2 in adipose tissue and can cause an increase in reduced glutathione.
“It can upregulate uncoupled proteins 2 (UCP2) in adipose tissue [102] and can also cause an increase in reduced glutathione [100].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [102]
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- Authors
- Anedda, A., Rial, E., & González-Barroso, M. M.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- ORCID
- Rial, Eduardo
- Venue
- Journal of Endocrinology
- Publisher
- Bioscientifica
- Published
- 2008-08-07
- Volume
- 199
- Issue
- 1
- Pages
- 33-40
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2162039295
- Cited by
- 98
- References
- 48
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 10 · 2014: 4 · 2013: 6 · 2012: 7
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Ministerio de Ciencia e Innovación (CSD2007-00020, BFU2006-08182)
- Regione Autonoma della Sardegna
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- metformin, UCP2, oxidative stress, white adipocytes, reactive oxygen species, aconitase activity, lipolysis, fatty acid oxidation, mitochondrial respiration inhibition, AMPK, type 2 diabetes, 3T3-L1 adipocytes, epididymal adipose tissue
- MeSH terms
- Uncoupling Protein 2, Animals, Cell Differentiation, Gene Expression Regulation, Hypoglycemic Agents, Ion Channels, Lipolysis, Metformin, Mice, Inbred C57BL, Blotting, Western, Oxidative Stress, Mitochondrial Proteins, 3T3-L1 Cells, Mice, Adipose Tissue, White, Adipocytes, White, In Vitro Techniques
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