Table1_Inhibition of PPARγ by BZ26, a GW9662 derivate, attenuated obesity-related breast cancer progression by inhibiting the reprogramming of mature adipocytes into to cancer associate adipocyte-like cells.DOCX

Obesity has been associated with the development of 13 different types of cancers, including breast cancer. Evidence has indicated that cancer-associated adipocytes promote the proliferation, invasion, and metastasis of cancer. However, the mechanisms that link CAAs to the progression of obesity-related cancer are still unknown. Here, we found the mature adipocytes in the visceral fat of HFD-fed mice have a CAAs phenotype but the stromal vascular fraction of the visceral fat has not. Importantly, we found the derivate of the potent PPARγ antagonist GW9662, BZ26 inhibited the reprogramming of mature adipocytes in the visceral fat of HFD-fed mice into CAA-like cells and inhibited the proliferation and invasion of obesity-related breast cancer. Further study found that it mediated the browning of visceral, subcutaneous and perirenal fat and attenuated inflammation of adipose tissue and metabolic disorders. For the mechanism, we found that BZ26 bound and inhibited PPARγ by acting as a new modulator. Therefore, BZ26 serves as a novel modulator of PPARγ activity, that is, capable of inhibiting obesity-related breast cancer progression by inhibiting of CAA-like cell formation, suggesting that inhibiting the reprogramming of mature adipocytes into CAAs or CAA-like cells may be a potential therapeutic strategy for obesity-related cancer treatment.

肥胖与13种不同类型的癌症发展相关，包括乳腺癌。已有证据表明，与癌症相关的脂肪细胞可促进癌细胞的增殖、侵袭和转移。然而，将癌症相关脂肪细胞（CAAs）与肥胖相关癌症进展相联系的具体机制尚不明确。在本研究中，我们发现高脂饮食（HFD）喂养的小鼠内脏脂肪中的成熟脂肪细胞具有CAAs表型，但其间质血管分数却未出现该表型。值得注意的是，我们发现强效PPARγ拮抗剂GW9662的衍生物BZ26能够抑制HFD喂养小鼠内脏脂肪中成熟脂肪细胞向CAAs样细胞的重编程，并抑制肥胖相关乳腺癌的增殖和侵袭。进一步研究显示，BZ26通过介导内脏、皮下和肾周脂肪的褐变作用，减轻了脂肪组织的炎症和代谢紊乱。在机制上，我们发现BZ26通过作为新的调节剂的作用与PPARγ结合并抑制其活性。因此，BZ26作为一种新型PPARγ活性调节剂，能够通过抑制CAAs样细胞的形成来抑制肥胖相关乳腺癌的进展，这表明抑制成熟脂肪细胞向CAAs或CAAs样细胞的重编程可能成为肥胖相关癌症治疗的一种潜在策略。