AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity
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Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.
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Dysregulation of adipose tissue metabolism has been previously linked to an age-related process of ECM deposition, and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms.
“Dysregulation of adipose tissue metabolism has been previously linked to an age‐related process of ECM deposition and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms (36, 259, 260).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [260]
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- Authors
- Luo, T., Nocon, A., Fry, J., Sherban, A., Rui, X., Jiang, B., Xu, X. J., Han, J., Yan, Y., Yang, Q., Li, Q., & Zang, M.
- Affiliations
- Boston University (US)
- Children's Mercy Hospital (US)
- University of California, Irvine (US)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Corresponding author
- Zang, Mengwei
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-05-13
- Volume
- 65
- Issue
- 8
- Pages
- 2295-2310
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4955985
- OpenAlex
- W2388453346
- Cited by
- 172
- References
- 47
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 14 · 2023: 12 · 2022: 23 · 2021: 23 · 2020: 20 · 2019: 8 · 2018: 22 · 2017: 18 · 2016: 6
- FWCI
- 16.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (RO1 DK076942, R01 DK100603, R21AA021181)
- American Diabetes Association Award (1-15-BS-216)
- Boston University Clinical and Translational Science Award (1UL1TR001430)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- metformin, AMPK activation, adipose tissue fibrosis, extracellular matrix remodeling, obesity, insulin resistance, TGF-β1/Smad3 signaling, collagen deposition, LOX, myofibroblast activation, adipocyte apoptosis, stromal vascular fraction, 3T3-L1 adipocytes, ob/ob mice, diet-induced obesity
- MeSH terms
- Adipose Tissue, Animals, Cells, Cultured, Collagen, Extracellular Matrix, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Mice, Inbred C57BL, Obesity, Signal Transduction, Mice, Adipose Tissue, White, Transforming Growth Factor beta1, AMP-Activated Protein Kinases, Myofibroblasts, In Vitro Techniques
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