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Targeting Pathologic Adipose Tissue Deposition In Secondary Lymphedema
Ziyu Chen, MD, PhD1, Mengfan Wu, MD, PhD1, John McNamara, BS2, Dennis Orgill, MD, PhD1, Indranil Sinha, MD, PhD1, Arin Greene, MD1, Shailesh Agarwal, MD1.
1Harvard Medical School, Boston, MA, USA, 2Rutgers University, Newark, NJ, USA.

PURPOSE: Secondary lymphedema is a pathological condition characterized by limb swelling and hypertrophy. In the United States, this condition impacts patients after lymph node dissection for treatment of breast, skin, gynecologic, and urologic cancers. Clinically, we note that patients with chronic secondary lymphedema exhibit progressive adipose tissue and fibrotic deposition in the affected extremity. Pre-adipocytes have been shown to be major contributors to adipose tissue inflammation due to their proliferative and fibrogenic phenotype. We hypothesize that a therapeutic strategy to induce the maturation of pre-adipocytes to mature adipocytes will paradoxically reduce fibroadipose tissue deposition. Here we treat mice with rosiglitazone after lymphadenectomy to augment signaling through peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipocyte differentiation and metabolism.
METHODS: A validated model of hindlimb lymphedema was employed with surgical excision of the ipsilateral superficial and deep inguinal lymph nodes and popliteal lymph node, and cauterization of the femoral lymphatic vessel; control mice received sham surgery (incise and suture the skin). The thickness of skin, subcutaneous adipose tissue, and underlying connective tissue were quantified using frozen sections at days 7, 14 and 21 after the surgery (n=4/timepoint). Separately, wild type mice with hind limb lymphedema were treated with i.p. PPARγ agonist (rosiglitazone: 10 mg/kg) or vehicle control; treatment was performed two days per week with first injection initiated on day of surgery (n=8/group). Size of the edema and circumference of the hind limb were measured every 3 days after the surgery (edema size = π width of limb height of limb 1/4).
RESULTS: Adipose tissue thickness remained elevated in experimental hindlimbs throughout 21 days after surgery relative to controls (day 7: 1.9 mm v. 0.7 mm, p<0.01; day 14: 2.4 mm v. 0.9 mm, p<0.05; day 21: 1.8 mm v. 0.9 mm, p<0.01) (Fig A). Rosiglitazone reduced edema relative to baseline at day 6 and day 9 when compared with no treatment (day 6: 108% v. 116%, p<0.01, day 9: 105% v. 112%, p<0.01). Hind limb circumference was decreased after the treatment of rosiglitazone (day 6: 3.9mm v. 4.0mm, p<0.05, day 9: 3.5mm v. 3.6mm, p=0.06) (Fig B). Rosiglitazone appeared to reduce fibrotic tissue deposition, skin thickness, and adipose tissue layer thickness relative to no treatment after lymphadenectomy (Fig C).
CONCLUSION: Our results verify the presence of progressive fibroadipose tissue deposition in a mouse model of secondary lymphedema which approximates surgical lymphadenectomy. Rosiglitazone, a potent agonist of PPARγ, demonstrates efficacy reducing limb size. Initial histologic evaluation suggests that this is due to a reduction in fibrosis and adipose tissue deposition. Further evaluation is required to verify maturity of adipocytes with rosiglitazone treatment by examining their transcriptomic profile and metabolic properties.


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