肥胖与13种不同类型的癌症发展有关，包括乳腺癌。证据表明，癌相关脂肪细胞促进癌症的增殖、侵袭和转移。然而，连接癌相关脂肪细胞与肥胖相关癌症进展的机制尚不清楚。在这里，我们发现高脂饮食喂养的小鼠内脏脂肪成熟脂肪细胞具有癌相关脂肪细胞表型，但内脏脂肪的基质血管组分却没有。重要的是，我们发现有效的PPARγ拮抗剂GW9662衍生物BZ26可抑制高脂饮食喂养的小鼠内脏脂肪中成熟脂肪细胞向癌相关脂肪细胞样细胞的转化，并抑制肥胖相关乳腺癌的增殖和侵袭。进一步的研究发现，它介导了内脏、皮下和围肾脂肪的棕化，并减轻了脂肪组织的炎症和代谢紊乱。关于机制，我们发现BZ26作为一种新的调节因子结合并抑制了PPARγ。因此，BZ26是PPARγ活性的一种新型调节因子，能通过抑制成熟脂肪细胞向癌相关脂肪细胞或类癌细胞的转化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癌相关脂肪细胞或类癌细胞的转化可能是肥胖相关癌症治疗的潜在策略。版权所有 © 2023 Li, Geng, Yu, Zhou, Zheng, Fu, Kong and Feng.

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.Copyright © 2023 Li, Geng, Yu, Zhou, Zheng, Fu, Kong and Feng.