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Updated: Jul 20, 2026
A Revised Method for Inducing Secondary Lymphedema in the Hindlimb of Mice
Published on: November 2, 2019
Metformin Eliminates Lymphedema in Mice by Alleviating Inflammation and Fibrosis: Implications for Human Therapy
Miaomiao Wei1, Liangliang Wang1, Xin Liu1
1From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University.
Background:
Secondary lymphedema is a chronic, disabling disease affecting more than 50% of patients with cancer and lacking effective pharmacologic treatment even for early to middle disease stages. Metformin reportedly exerts anti-inflammatory and antifibrotic effects and is safe, with minimal side effects. The authors investigated the role of metformin in lymphedema mouse models and examined underlying molecular mechanisms.
Methods:
Male C57BL/6 mice (6 to 8 weeks old; n = 15/group) received metformin (300 mg/kg/day) by gavage on day 3 after lymphedema surgery; saline and sham groups were administered the same volume of saline. Hindlimb circumference and tail volume were monitored every 2 days. On day 28, samples were collected for histologic assessment, Western blotting, and reverse transcription quantitative polymerase chain reaction analysis of inflammation, fibrosis, and AMP-activated protein kinase (AMPK) expression. AMPK activity was assayed in patients with secondary lymphedema (International Society of Lymphology stage II) and controls following strict inclusion criteria.
Results:
Compared with the saline group, the metformin group exhibited hindlimb circumference and tail volume reduced by 469.70% and 305.18%, respectively, on day 28. Dermal thickness was reduced by 38.27% and 72.57% in the hindlimbs and tail, respectively. Metformin decreased CD4+ T-cell infiltration by 19.73%, and decreased expression levels of interleukin-4, interleukin-13, interleukin-17, and transforming growth factor-β1. In addition, it lowered collagen I deposition by 33.18%. Compared with the saline group, the number of lymphatic vessels increased by 229.96% in the metformin group. Both the saline group mice and patients with lymphedema showed reduced AMPK activity; metformin increased p-AMPK expression by 106.12%.
Conclusion:
Metformin alleviated inflammation and fibrosis and increased lymphangiogenesis in lymphedema mouse models by activating AMPK signaling.
Clinical Relevance Statement:
Metformin provides preliminary evidence as a potential therapeutic option for lymphedema.
Insights
Metformin significantly reduced lymphedema symptoms in mice by decreasing inflammation and fibrosis. This study suggests metformin as a potential treatment for lymphedema by activating AMP-activated protein kinase (AMPK) signaling.
Area of Science:
- Biomedical Science
- Pharmacology
- Oncology
Background:
- Secondary lymphedema is a chronic condition affecting over 50% of cancer patients, with limited pharmacologic treatments.
- Metformin, known for its anti-inflammatory and antifibrotic properties, offers a safe profile with minimal side effects.
Purpose of the Study:
- To investigate the efficacy of metformin in lymphedema mouse models.
- To elucidate the underlying molecular mechanisms of metformin's action in lymphedema.
Main Methods:
- Male C57BL/6 mice received metformin (300 mg/kg/day) or saline post-lymphedema surgery.
- Measurements included hindlimb circumference, tail volume, dermal thickness, and histological analysis.
- Inflammation, fibrosis, and AMP-activated protein kinase (AMPK) expression were assessed via Western blotting and RT-qPCR.
Main Results:
- Metformin treatment significantly reduced hindlimb circumference (469.70%) and tail volume (305.18%) compared to saline.
- Histological analysis showed decreased dermal thickness, T-cell infiltration, and collagen I deposition.
- Metformin increased lymphatic vessel count and activated AMPK signaling, evidenced by increased p-AMPK expression.
Conclusions:
- Metformin effectively alleviates inflammation and fibrosis while promoting lymphangiogenesis in lymphedema mouse models.
- Activation of AMPK signaling is the key mechanism by which metformin exerts its therapeutic effects.
- Metformin shows promise as a potential therapeutic agent for secondary lymphedema.
